Sustained-release drug delivery systems comprising an intraocular pressure lowering agent, a cnp compound, an npr-b compound, a tie-2 agonist, or neurotrophic agent for use for treating glaucoma or ocular hypertension

ABSTRACT

This disclosure relates to a drug delivery system comprising an intraocular pressure lowering agent, a neurotrophic agent, such as a CNTF compound, a C-type Natriuretic Peptide (CNP) compound, a Tie-2 agonist, a Natriuretic Peptide Receptor-B (NPR-B) compound, or an apoptosis signaling fragment inhibitor (FAS) or FAS-ligand (FASL) inhibitor, including any combination of these compounds and a sustained delivery component. Methods of treating a glaucoma or related conditions, medicaments, kits, uses and methods of manufacturing are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of United States ProvisionalApplication Nos. 62/687,172, filed Jun. 19, 2018, 62/726,029, filed Aug.31, 2018, and 62/747,060, filed Oct. 17, 2018, which are incorporated byreference herein in their entirety. Application C4019.10002WO01, filedJun. 18, 2019, is also incorporated by reference herein in its entirety.A PCT application being concurrently filed on Jun. 18, 2019 under docketnumber C4019.10002WO01, with inventors Rhett M. Schiffman and LukasScheibler, is also incorporated by reference herein in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jun. 17, 2019, isnamed V3563_10001 WO01_SL.txt and is 4,008 bytes in size.

SUMMARY

This disclosure relates to a drug delivery system comprising anintraocular pressure lowering agent, a neurotrophic agent, such as aCNTF compound, a C-type Natriuretic Peptide (CNP) compound, a Tie-2agonist, a Natriuretic Peptide Receptor-B (NPR-B) compound, or anapoptosis signaling fragment inhibitor (FAS) or FAS-ligand (FASL)inhibitor, including any combination of these compounds and a sustaineddelivery component. This type of drug delivery system can be used totreat a glaucoma or ocular hypertension.

Some embodiments include a drug delivery system comprising: a firstactive pharmaceutical ingredient (API) and a sustained deliverycomponent, wherein the first API is an intraocular pressure loweringagent, a neurotrophic agent, a C-type Natriuretic Peptide (CNP), aNatriuretic Peptide Receptor-B (NPR-B), an apoptosis signaling fragment(FAS) inhibitor or a FAS-ligand (FASL) inhibitor, or a combinationthereof.

Some embodiments include a method of treating a glaucoma comprisingadministering a drug delivery system of described herein to a mammal insuffering from glaucoma or ocular hypertension.

Some embodiments include use of an intraocular pressure lowering agent,a neurotrophic agent, a CNP, a NPR-B, a FAS inhibitor or a FASLinhibitor, or a combination thereof, in the manufacture of a drugdelivery system described herein for the treatment of glaucoma or ocularhypertension.

Some embodiments include a kit comprising a drug delivery systemdescribed herein and a label with instructions for use of the drugdelivery system for the treatment of a glaucoma.

DETAILED DESCRIPTION

With respect to a drug delivery system comprising an intraocularpressure lowering agent, a neurotrophic agent, such as a CNTF compound,a CNP compound, a NPR-B compound, or a FAS or FASL inhibitor (referredto herein as “subject drug delivery system”), and a sustained deliverycomponent, any suitable prostaglandin receptor agonist, prostanoidreceptor agonist, or any suitable prostaglandin compound, including anyprostaglandin acid form (e.g. the acid obtained by hydrolyzingprostaglandin esters), any prostaglandin salt form, or any prostaglandinester prodrug, may be used. Examples include bimatoprost (amide) or thebimatoprost acid, i.e. the carboxylic acid obtained when the amide groupis hydrolyzed, travoprost, travoprost acid, latanoprost, latanoprostacid, latanoprostene, tafluprost, tafluprost acid, etc., a prostaglandinEP2 agonist, a prostaglandin EP3 agonist, or a combination thereof.

Any suitable amount of a prostaglandin compound, such as bimatoprost,bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprostacid, latanoprostene, tafluprost, tafluprost acid, etc., a prostaglandinEP2 agonist, or a prostaglandin EP3 agonist, may be used in the drugdelivery system. For example, a drug delivery system may contain about0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about 50-60 μg,about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90-100 μg, about0.010-30 μg, about 30-60 μg, about 60-100 μg, about 0.01-100 μg, about0.010-100 μg, about 100-200 μg, about 200-300 μg, about 300-400 μg,about 400-500 μg, about 500-600 μg, about 600-700 μg, about 700-800 μg,about 800-900 μg, about 900-1,000 μg, about 0.01-300 μg, about 300-600μg, about 600-1,000 μg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg,about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg,about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6mg, about 6-10 mg, or about 0.01-10 mg of one of these compounds. Theseamounts may also apply to a situation where the drug is present in acovalently bonded form, such as to another drug or to the sustaineddelivery component. For example, a compound of Formula 1 or Formula 3may be said to contain 1 mg of the prostaglandin compound even thoughthe prostaglandin is covalently bound to other parts of the drugdelivery system.

Use of the amounts given above for a prostaglandin compound, such asbimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost,latanoprost acid, latanoprostene, tafluprost, tafluprost acid, etc., aprostaglandin EP2 agonist, or a prostaglandin EP3 agonist, in a drugdelivery system, may provide a drug delivery system that providestherapeutic levels of the prostaglandin compound for about 1-4 weeks,about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months,about 12-18 months, about 18-24 months, about 2-5 years, about 5-10years, or longer.

In some embodiments, the prostaglandin receptor agonist, prostanoidreceptor agonist, or prostaglandin compound is bimatoprost (amide) orthe bimatoprost acid. In some embodiments, the prostaglandin receptoragonist or prostaglandin compound is travoprost. In some embodiments,the prostaglandin receptor agonist or prostaglandin compound istravoprost acid. In some embodiments, the prostaglandin receptor agonistor prostaglandin compound is latanoprost. In some embodiments, theprostaglandin receptor agonist or prostaglandin compound is latanoprostacid. In some embodiments, the prostaglandin receptor agonist orprostaglandin compound is latanoprostene. In some embodiments, theprostaglandin receptor agonist or prostaglandin compound is tafluprost.In some embodiments, the prostaglandin receptor agonist or prostaglandincompound is tafluprost acid. In some embodiments, the prostaglandinreceptor agonist or prostaglandin compound is a prostaglandin EP2receptor agonist. In some embodiments, the prostaglandin receptoragonist or prostaglandin compound is a prostaglandin EP3 receptoragonist.

Some subject drug delivery systems may include an intraocular pressurelowering agent, such as a beta blocker, an alpha agonist, a carbonicanhydrase inhibitor, a Rho Kinase inhibitor, a cannabinoid receptoragonist, etc. Some subject drug delivery systems may include two or moreintraocular pressure lowering agents, such as a prostaglandin compound,a prostaglandin receptor agonist, or a prostanoid receptor agonist; abeta blocker; an alpha agonist; a carbonic anhydrase inhibitor; acannabinoid receptor agonist; a Rho kinase inhibitor; etc. Some subjectdrug delivery systems contain two or more of: a prostaglandin receptoragonist (or a prostaglandin compound or prostanoid receptor agonist), abeta blocker, an alpha agonist, a carbonic anhydrase inhibitor, acannabinoid receptor agonist, a Rho kinase inhibitor, etc.

With respect to a subject drug delivery system, any suitable betablocker, or any suitable beta adrenergic antagonist, may be used.Examples include timolol, betaxolol, levobunolol, metipranolol, etc., ora combination thereof. In some embodiments, the beta blocker is timolol.In some embodiments, the beta blocker is betaxolol. In some embodiments,the beta blocker is levobunolol. In some embodiments, the beta blockeris metipranolol.

Any suitable amount of a beta blocker or a beta adrenergic antagonist,such as timolol, betaxolol, levobunolol, or metipranolol, may be used inthe drug delivery system. For example, a drug delivery system maycontain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg,about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90-100μg, about 0.01-30 μg, about 30-60 μg, about 60-100 μg, about 0.01-100μg, about 0.01-100 μg, about 100-200 μg, about 200-300 μg, about 300-400μg, about 400-500 μg, about 500-600 μg, about 600-700 μg, about 700-800μg, about 800-900 μg, about 900-1,000 μg, about 0.01-300 μg, about300-600 μg, about 600-1,000 μg, about 0.01-1 mg, about 0.1-1 mg, about1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg,about 3-6 mg, about 6-10 mg, or about 0.01-10 mg of one of thesecompounds. These amounts may also apply to a situation where the drug ispresent in a covalently bonded form, such as to another drug or to thesustained delivery component.

Use of the amounts given above for a beta blocker or a beta adrenergicantagonist, such as timolol, betaxolol, levobunolol, or metipranolol, ina drug delivery system, may provide a drug delivery system that providestherapeutic levels of the beta blocker or the beta adrenergic antagonistfor about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9months, about 9-12 months, about 12-18 months, about 18-24 months, about2-5 years, about 5-10 years, or longer.

With respect to a subject drug delivery system, any suitable alphaagonist, or alpha adrenergic agonist, may be used. Examples includebrimonidine, apraclonidine, etc., or a combination thereof. In someembodiments, the alpha agonist is brimonidine. In some embodiments, thealpha agonist is apraclonidine.

Any suitable amount of an alpha agonist or an alpha adrenergic agonistsuch as brimonidine, apraclonidine, etc., may be used in the drugdelivery system. For example, a drug delivery system may contain about0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about 50-60 μg,about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90-100 μg, about0.01-30 μg, about 30-60 μg, about 60-100 μg, about 0.01-100 μg, about0.1-100 μg, about 100-200 μg, about 200-300 μg, about 300-400 μg, about400-500 μg, about 500-600 μg, about 600-700 μg, about 700-800 μg, about800-900 μg, about 900-1,000 μg, about 0.01-300 μg, about 300-600 μg,about 600-1,000 μg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg,about 6-10 mg, or about 0.01-10 mg of one of these compounds. Theseamounts may also apply to a situation where the drug is present in acovalently bonded form, such as to another drug or to the sustaineddelivery component.

Use of the amounts given above for an alpha agonist or an alphaadrenergic agonist such as brimonidine, apraclonidine, etc., in a drugdelivery system, may provide a drug delivery system that providestherapeutic levels of the alpha agonist or the alpha adrenergic agonistfor about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9months, about 9-12 months, about 12-18 months, about 18-24 months, about2-5 years, about 5-10 years, or longer.

With respect to a subject drug delivery system, any suitable carbonicanhydrase inhibitor may be used. Examples include brinzolamide,acetazolamide, dorzolamide, methazolamide, etc., or a combinationthereof. In some embodiments, the carbonic anhydrase inhibitor isbrinzolamide. In some embodiments, the carbonic anhydrase inhibitor isacetazolamide. In some embodiments, the carbonic anhydrase inhibitor isdorzolamide. In some embodiments, the carbonic anhydrase inhibitor ismethazolamide.

Any suitable amount of a carbonic anhydrase inhibitor such asbrinzolamide, acetazolamide, dorzolamide, methazolamide, etc., may beused in the drug delivery system. For example, a drug delivery systemmay contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg,about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg,about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about0.01-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg,about 90-100 μg, about 0.01-30 μg, about 30-60 μg, about 60-100 μg,about 0.01-100 μg, about 0.1-100 μg, about 100-200 μg, about 200-300 μg,about 300-400 μg, about 400-500 μg, about 500-600 μg, about 600-700 μg,about 700-800 μg, about 800-900 μg, about 900-1,000 μg, about 0.01-300μg, about 300-600 μg, about 600-1,000 μg, about 0.01-1 mg, about 0.1-1mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg of one ofthese compounds. These amounts may also apply to a situation where thedrug is present in a covalently bonded form, such as to another drug orto the sustained delivery component.

Use of the amounts given above for a carbonic anhydrase inhibitor suchas brinzolamide, acetazolamide, dorzolamide, methazolamide, etc., in adrug delivery system, may provide a drug delivery system that providestherapeutic levels of the carbonic anhydrase inhibitor for about 1-4weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12months, about 12-18 months, about 18-24 months, about 2-5 years, about5-10 years, or longer.

With respect to a subject drug delivery system, any suitable cholinergicmay be used. Examples include pilocarpine, carbachol, etc., or acombination thereof. In some embodiments, the cholinergic may bepilocarpine. In some embodiments, the cholinergic may be carbachol.

Any suitable amount of a cholinergic, such as pilocarpine, carbachol,etc., may be used in the drug delivery system. For example, a drugdelivery system may contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg,about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg,about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10μg, about 0.01-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg,about 40-50 μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about80-90 μg, about 90-100 μg, about 0.01-30 μg, about 30-60 μg, about60-100 μg, about 0.01-100 μg, about 0.1-100 μg, about 100-200 μg, about200-300 μg, about 300-400 μg, about 400-500 μg, about 500-600 μg, about600-700 μg, about 700-800 μg, about 800-900 μg, about 900-1,000 μg,about 0.01-300 μg, about 300-600 μg, about 600-1,000 μg, about 0.01-1mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg ofone of these compounds. These amounts may also apply to a situationwhere the drug is present in a covalently bonded form, such as toanother drug or to the sustained delivery component.

Use of the amounts given above for a cholinergic, such as pilocarpine,carbachol, etc., in a drug delivery system, may provide a drug deliverysystem that provides therapeutic levels of the cholinergic for about 1-4weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12months, about 12-18 months, about 18-24 months, about 2-5 years, about5-10 years, or longer.

With respect to a subject drug delivery system, any suitable Rho kinaseinhibitor, such as netarsudil, may be used. In some embodiments, the Rhokinase inhibitor is netarsudil.

Any suitable amount of a Rho kinase inhibitor, such as netarsudil, maybe used in the drug delivery system. For example, a drug delivery systemmay contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg,about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg,about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about0.01-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg,about 90-100 μg, about 0.01-30 μg, about 30-60 μg, about 60-100 μg,about 0.01-100 μg, about 0.1-100 μg, about 100-200 μg, about 200-300 μg,about 300-400 μg, about 400-500 μg, about 500-600 μg, about 600-700 μg,about 700-800 μg, about 800-900 μg, about 900-1,000 μg, about 0.01-300μg, about 300-600 μg, about 600-1,000 μg, about 0.01-1 mg, about 0.1-1mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg of one ofthese compounds. These amounts may also apply to a situation where thedrug is present in a covalently bonded form, such as to another drug orto the sustained delivery component.

Use of the amounts given above fora Rho kinase inhibitor, such asnetarsudil, in a drug delivery system, may provide a drug deliverysystem that provides therapeutic levels of the Rho kinase inhibitor forabout 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months,about 9-12 months, about 12-18 months, about 18-24 months, about 2-5years, about 5-10 years, or longer.

With respect to a subject drug delivery system, any suitable Tie-2agonist may be used, such as angiopoietin-1, angiopoietin-2,angiopoietin-3, angiopoietin-4, etc.

Any suitable amount of a Tie-2 agonist, such as angiopoietin-1,angiopoietin-2, angiopoietin-3, angiopoietin-4, etc., may be used in thedrug delivery system. For example, a drug delivery system may containabout 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg,about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg,about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about 50-60μg, about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90-100 μg,about 0.01-30 μg, about 30-60 μg, about 60-100 μg, about 0.01-100 μg,about 0.1-100 μg, about 100-200 μg, about 200-300 μg, about 300-400 μg,about 400-500 μg, about 500-600 μg, about 600-700 μg, about 700-800 μg,about 800-900 μg, about 900-1,000 μg, about 0.0100-300 μg, about 300-600μg, about 600-1,000 μg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg,about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg,about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6mg, about 6-10 mg, or about 0.01-10 mg of one of these compounds. Theseamounts may also apply to a situation where the drug is present in acovalently bonded form, such as to another drug or to the sustaineddelivery component.

Use of the amounts given above for Tie-2 agonist, such asangiopoietin-1, angiopoietin-2, angiopoietin-3, angiopoietin-4, etc., ina drug delivery system, may provide a drug delivery system that providestherapeutic levels of the Tie-2 agonist for about 1-4 weeks, about 1-3months, about 3-6 months, about 6-9 months, about 9-12 months, about12-18 months, about 18-24 months, about 2-5 years, about 5-10 years, orlonger.

With respect to a subject drug delivery system, a neurotrophic agent caninclude a CNTF compound or another neurotrophic agent, a CNTF compoundincludes any compound having a structure or activity similar to Ciliaryneurotrophic factor (CNTF), including CNTF, protein derivatives of CNTF,or a CNTF peptide. Examples include CNTF, a peptide containing part ofthe CNTF sequence, such as Peptide 6 (P6; Ac-VGDGGLFEKKL-NH2 (SEQ ID NO:1)) and Peptide 21 (P21; Ac-DGGL^(A)G-NH2 (SEQ ID NO: 2)), recombinantCNTF (rhCNTF), or a neurotrophic peptide identified in U.S. Pat. No.8,592,374, which is incorporated herein by reference for its disclosurerelated to neurotrophic peptides, including neurotrophic peptides havingan adamantly group at the C- and/or N-terminal end, or any other peptidehaving similar biological activity to CNTF. Other neurotrophic agentsinclude nerve growth factor (NGF), Brain-derived neurotrophic factor(BDNF), glial cell-derived neurotrophic factor (GDNF), etc.

Any suitable amount of a neurotrophic agent, such as a CNTF compound,NGF, BDNF, GDNF, etc., may be used in the drug delivery system. Forexample, a drug delivery system may contain about 0.01-1 μg, about 1-2μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg, about 20-30 μg,about 30-40 μg, about 40-50 μg, about 50-60 μg, about 60-70 μg, about70-80 μg, about 80-90 μg, about 90-100 μg, about 0.01-30 μg, about 30-60μg, about 60-100 μg, about 0.01-100 μg, about 0.1-100 μg, about 100-200μg, about 200-300 μg, about 300-400 μg, about 400-500 μg, about 500-600μg, about 600-700 μg, about 700-800 μg, about 800-900 μg, about900-1,000 μg, about 0.01-300 μg, about 300-600 μg, about 600-1,000 μg,about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg, orabout 0.01-10 mg of one of these compounds. These amounts may also applyto a situation where the drug is present in a covalently bonded form,such as to another drug or to the sustained delivery component.

Use of the amounts given above for a neurotrophic agent, such as a CNTFcompound, NGF, BDNF, GDNF, etc., in a drug delivery system, may providea drug delivery system that provides therapeutic levels of theneurotrophic agent for about 1-4 weeks, about 1-3 months, about 3-6months, about 6-9 months, about 9-12 months, about 12-18 months, about18-24 months, about 2-5 years, about 5-10 years, or longer.

With respect to a subject drug delivery system, a CNP compound includesany compound having a structure or activity similar to C-typeNatriuretic Peptide, including natural C-type Natriuretic Peptide.

Any suitable amount of a CNP compound, such as natural CNP, may be usedin the drug delivery system. For example, a drug delivery system maycontain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg,about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90-100μg, about 0.01-30 μg, about 30-60 μg, about 60-100 μg, about 0.01-100μg, about 0.1-100 μg, about 100-200 μg, about 200-300 μg, about 300-400μg, about 400-500 μg, about 500-600 μg, about 600-700 μg, about 700-800μg, about 800-900 μg, about 900-1,000 μg, about 0.01-300 μg, about300-600 μg, about 600-1,000 μg, about 0.01-1 mg, about 0.1-1 mg, about1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg,about 3-6 mg, about 6-10 mg, or about 0.01-10 mg of one of thesecompounds. These amounts may also apply to a situation where the drug ispresent in a covalently bonded form, such as to another drug or to thesustained delivery component.

Use of the amounts given above for a CNP compound, such as natural CNP,in a drug delivery system, may provide a drug delivery system thatprovides therapeutic levels of the CNP compound for about 1-4 weeks,about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months,about 12-18 months, about 18-24 months, about 2-5 years, about 5-10years, or longer.

With respect to a subject drug delivery system, an NPR-B compoundincludes any compound having a structure or activity similar toNatriuretic Peptide Receptor-B, including natural Natriuretic PeptideReceptor-B.

Any suitable amount of a NPR-B compound, such as natural NPR-B, may beused in the drug delivery system. For example, a drug delivery systemmay contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg,about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg,about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about0.01-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg,about 90-100 μg, about 0.01-30 μg, about 30-60 μg, about 60-100 μg,about 0.01-100 μg, about 0.1-100 μg, about 100-200 μg, about 200-300 μg,about 300-400 μg, about 400-500 μg, about 500-600 μg, about 600-700 μg,about 700-800 μg, about 800-900 μg, about 900-1,000 μg, about 0.01-300μg, about 300-600 μg, about 600-1,000 μg, about 0.01-1 mg, about 0.1-1mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg of one ofthese compounds. These amounts may also apply to a situation where thedrug is present in a covalently bonded form, such as to another drug orto the sustained delivery component.

Use of the amounts given above for a NPR-B compound, such as naturalNPR-B, in a drug delivery system, may provide a drug delivery systemthat provides therapeutic levels of the NPR-B compound for about 1-4weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12months, about 12-18 months, about 18-24 months, about 2-5 years, about5-10 years, or longer.

Useful FAS or FASL inhibitors include bicyclol, FLIP; MET12(HHIYLGAVNYIY (SEQ ID NO: 3), HHIYLGATNYIY (SEQ ID NO: 4), orH⁶⁰HIYLGATNYIY⁷¹ (SEQ ID NO: 4)), or a shorter fragment thereof, such asa tetramer having a sequence YLGA (SEQ ID NO: 5), or a fragment having asequence homology of at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70%, at least about 80%, or at least about 90% sequencehomology to MET12, including compound having a sequence shown in Table 1below, such as compound 1, compound 2, compound 3, compound 4, compound5, compound 6, compound 7, compound 8, compound 9, compound 10, orcompound 11, ON L1204 (e.g. a peptide comprising or consisting of asequence HHIYLGATNYIY (SEQ ID NO: 4)); other MET12 derivatives such as acompound having a sequence: H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4), FASapoptotic inhibitory molecule [FAIM]; NOL3 [nucleolar protein 3(apoptosis repressor with CARD domain [ARC]), etc.]; DcR1; DcR2; orDcR3.

TABLE 1 Compound Sequence SEQ ID NO:  1 YLGA  5  2 IYLGA  6  3 YLGAV  7 4 HIYLGA  8  5 IYLGAV  9  6 HIYLGAV 10  7 IYLGAVN 11  8 HHIYLGA 12  9YLGAVNY 13 10 HHIYLGAV 14 11 YLGAVNYI 15

Any suitable amount of a FAS or FASL inhibitor, such as bicyclol, FLIP,compound 1, compound 2, compound 3, compound 4, compound 5, compound 6,compound 7, compound 8, compound 9, compound 10, or compound 11,ONL1204, H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4), FAIM, NOL3, DcR1, DcR2,DcR3, etc., may be used in the drug delivery system. For example, a drugdelivery system may contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg,about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg,about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10μg, about 0.01-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg,about 40-50 μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about80-90 μg, about 90-100 μg, about 0.01-30 μg, about 30-60 μg, about60-100 μg, about 0.01-100 μg, about 0.1-100 μg, about 100-200 μg, about200-300 μg, about 300-400 μg, about 400-500 μg, about 500-600 μg, about600-700 μg, about 700-800 μg, about 800-900 μg, about 900-1,000 μg,about 0.0100-300 μg, about 300-600 μg, about 600-1,000 μg, about 0.01-1mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg ofone of these compounds. These amounts may also apply to a situationwhere the drug is present in a covalently bonded form, such as toanother drug or to the sustained delivery component.

Use of the amounts given above for a FAS or FASL inhibitor, such asbicyclol, FLIP, compound 1, compound 2, compound 3, compound 4, compound5, compound 6, compound 7, compound 8, compound 9, compound 10, orcompound 11, ONL1204, H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4), FAIM, NOL3,DcR1, DcR2, DcR3, etc., in a drug delivery system, may provide a drugdelivery system that provides therapeutic levels of the NPR-B compoundfor about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9months, about 9-12 months, about 12-18 months, about 18-24 months, about2-5 years, about 5-10 years, or longer.

Table 2 below depicts drug combinations that are of particular interestin a subject drug delivery system.

TABLE 2 Drug 1 Drug 2 PG beta blocker PG alpha agonist PG carbonicanhydrase inhibitor PG Rho Kinase inhibitor beta blocker alpha agonistbeta blocker carbonic anhydrase inhibitor beta blocker Rho Kinaseinhibitor alpha agonist carbonic anhydrase inhibitor alpha agonist RhoKinase inhibitor carbonic anhydrase inhibitor Rho Kinase inhibitorintraocular pressure lowering agent neurotrophic agent intraocularpressure lowering agent CNTF compound intraocular pressure loweringagent CNP compound intraocular pressure lowering agent NPR-B compoundCNTF compound CNP compound CNTF compound NPR-B compound CNTF compound PGCNTF compound beta blocker CNTF compound alpha agonist CNTF compoundcarbonic anhydrase inhibitor CNTF compound Rho Kinase inhibitor CNPcompound NPR-B compound CNP compound PG CNP compound beta blocker CNPcompound alpha agonist CNP compound carbonic anhydrase inhibitor CNPcompound Rho Kinase inhibitor NPR-B compound PG NPR-B compound betablocker NPR-B compound alpha agonist NPR-B compound carbonic anhydraseinhibitor NPR-B compound Rho Kinase inhibitor Tie-2 agonist PG Tie-2agonist beta blocker Tie-2 agonist alpha agonist Tie-2 agonist carbonicanhydrase inhibitor Tie-2 agonist Rho Kinase inhibitor Tie-2 agonistcannabinoid receptor agonist Tie-2 agonist CNTF compound Tie-2 agonistCNP compound Tie-2 agonist NPR-B compound Cannabinoid receptor agonistPG Cannabinoid receptor agonist beta blocker Cannabinoid receptoragonist alpha agonist Cannabinoid receptor agonist carbonic anhydraseinhibitor Cannabinoid receptor agonist Rho Kinase inhibitor Cannabinoidreceptor agonist CNTF compound Cannabinoid receptor agonist CNP compoundCannabinoid receptor agonist NPR-B compound Neurotrophic agent CNPcompound Neurotrophic agent NPR-B compound Neurotrophic agent PGNeurotrophic agent beta blocker Neurotrophic agent alpha agonistNeurotrophic agent carbonic anhydrase inhibitor Neurotrophic agent RhoKinase inhibitor FAS or FASL inhibitor PG FAS or FASL inhibitor betablocker FAS or FASL inhibitor alpha agonist FAS or FASL inhibitorcarbonic anhydrase inhibitor FAS or FASL inhibitor Rho Kinase inhibitorFAS or FASL inhibitor cannabinoid receptor agonist FAS or FASL inhibitorCNTF compound FAS or FASL inhibitor CNP compound FAS or FASL inhibitorNPR-B compound FAS or FASL inhibitor Tie-2 agonistPG: prostaglandin compound or prostaglandin receptor agonist, includingacid, salt, and ester or ester prodrug forms

Some drug delivery systems include a combination of bimatoprost acid andbicyclol, which is either directly covalently bonded, bonded with alinking group, or wherein both are bonded to a polymer or to asilicon-based drug delivery particle.

With respect to a subject drug delivery system comprising aprostaglandin receptor agonist or a prostaglandin compound and anintraocular pressure lowering agent, in some embodiments, theprostaglandin receptor agonist is covalently bound to the intraocularpressure lowering agent. In some embodiments, the prostaglandin receptoragonist is covalently bound to the intraocular pressure lowering agentvia a linking group.

For example, some compounds containing a prostaglandin compound or aprostaglandin receptor agonist covalently bound to an intraocularpressure lowering agent by a linking group are represented by Formula 1or 1A:

PG-L-IOP   Formula 1

IOP-L-IOP   Formula 1A

wherein PG-H or PG-OH is a prostaglandin receptor agonist, such as aprostaglandin compound or prostaglandin receptor agonist recited above;and each IOP-H or IOP-OH is independently an intraocular pressurelowering agent, such as an intraocular pressure lowering agent recitedabove.

With respect to a subject drug delivery system comprising both theprostaglandin receptor agonist and the neurotrophic agent, such as theCNTF compound, in some embodiments, the prostaglandin receptor agonistand the neurotrophic agent, such as the CNTF compound, are covalentlybound to one another. In some embodiments, the prostaglandin receptoragonist and the neurotrophic agent, such as the CNTF compound, arecovalently bound to one another via a linking group.

Some subject drug delivery systems comprise both the intraocularpressure lowering agent and the neurotrophic agent, such as the CNTFcompound. In some embodiments, the intraocular pressure lowering agentand the neurotrophic agent, such as the CNTF compound, are covalentlybound to one another. In some embodiments, the intraocular pressurelowering agent and the neurotrophic agent, such as the CNTF compound,are covalently bound to one another via a linking group.

Some subject drug delivery systems comprise both the intraocularpressure lowering agent and the CNP compound. In some embodiments, theintraocular pressure lowering agent and the CNP compound are covalentlybound to one another. In some embodiments, the intraocular pressurelowering agent and the CNP compound are covalently bound to one anothervia a linking group.

Some subject drug delivery systems comprise the intraocular pressurelowering agent and the NPR-B compound. In some embodiments, theintraocular pressure lowering agent and the NPR-B compound arecovalently bound to one another. In some embodiments, the intraocularpressure lowering agent and the NPR-B compound are covalently bound toone another via a linking group.

Some subject drug delivery systems comprise both the neurotrophic agent,such as the CNTF compound, and the CNP compound. In some embodiments,the neurotrophic agent, such as the CNTF compound, and the CNP compoundare covalently bound to one another. In some embodiments, theneurotrophic agent, such as the CNTF compound, and the CNP compound arecovalently bound to one another via a linking group.

Some subject drug delivery systems comprise both the neurotrophic agent,such as the CNTF compound, and the NPR-B compound. In some embodiments,the neurotrophic agent, such as the CNTF compound, and the NPR-Bcompound are covalently bound to one another. In some embodiments, theneurotrophic agent, such as the CNTF compound, and the NPR-B compoundare covalently bound to one another via a linking group.

Some subject drug delivery systems comprise both and the CNP compoundand the NPR-B compound. In some embodiments, the CNP compound and theNPR-B compound are covalently bound to one another. In some embodiments,the CNP compound and the NPR-B compound are covalently bound to oneanother via a linking group.

For example, some compounds containing a prostaglandin compound or aprostaglandin receptor covalently bound to a CNTF compound by a linkinggroup are represented by Formula 2:

PG-L-CNTF   Formula 2

wherein PG-H or PG-OH is a prostaglandin receptor agonist, such as aprostaglandin compound or prostaglandin receptor agonist recited above;and CNTF-H or CNTF-OH is a CNTF compound, such as a CNTF compoundrecited above.

Other covalently linked compounds include compounds represented byFormula 2A, 2B, 2C, 2D, 2E, or 2F:

IOP-L-CNTF   Formula 2A

IOP-L-CNP   Formula 2B

IOP-L-NPRB   Formula 2C

CNTF-L-CNP   Formula 2D

CNTF-L-NPRB   Formula 2E

CNP-L-NPRB   Formula 2F

Wherein IOP-H is intraocular pressure lowering agent, such as anintraocular pressure lowering agent recited above; CNTF-H or CNTF-OH isa CNTF compound, such as a CNTF compound recited above; CNP-H or CNP-OHis a CNP compound; and NPR-H or NPR-OH is a NPR-B compound.

With respect to any relevant structural representation, such as Formula1, 2, 2A, 2B, 2C, 2D, 2E, 2F, 3, 4, 5, 3D, 4D, or 5D (Formulas 3-5 and3D-5D are depicted below), L is a linking group represented by theempirical formula C_(a)H_(b)O_(c)N_(d) or C_(a)H_(b)O_(c).

With respect to any L, a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20. In some embodiments, a is 1-5, 5-10,10-15, 15-20, 1-10, or 10-20.

With respect to any L, b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43. In some embodiments,b is 1-10, 10-20, 20-30, 30-40, 40-43, 1-15, 15-30, or 30-43.

With respect to any L, c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, c is 0-2, 2-4, 4-6, 6-8, 8-10, 0-3, 3-6, or 6-10.

With respect to any L, d is 0, 1, or 2. In some embodiments, d is 0. Insome embodiments, d is 1. In some embodiments, d is 2.

In some embodiments, L may be represented by Formula L-1, L-2, L-3, L-4,L-5, L-6, L-7, or L-8:

With respect to any relevant structural representation, such as FormulaL-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, L1 may be represented by theempirical formula C_(e)H_(f)O_(g)N_(h) or C_(e)H_(f)O_(g).

With respect to any L¹, e is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, or 18. In some embodiments, e is 1-5, 5-10, 10-15,15-18, 1-10, or 10-18.

With respect to any L¹, f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, or 38. In some embodiments, f is 1-10, 10-20,20-30, 30-38, 1-15, 15-30, or 30-38.

With respect to any L¹, g is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In someembodiments, g is 0-2, 2-4, 4-6, 6-8, 0-3, 3-6, or 6-8.

With respect to any L¹, h is 0, 1, or 2. In some embodiments, h is 0. Insome embodiments, h is 1. In some embodiments, h is 2.

With respect to any relevant structural representation, such as FormulaL-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, in some embodiments L1 maybe:

—(CH₂)_(i)—(OCH₂CH₂)_(j)—O—(CH₂)_(k)—  [Formula L¹-1],

—(CH₂)_(i)—(OCH₂CH₂)_(j)—O—CONH—(CH₂)_(k)—  [Formula L¹-2],

—(C_(i)H_(2i))—(OCH₂CH₂)_(j)—O—(C_(k)H_(2k))—  [Formula L¹-3],

—(C_(i)H_(2i))—(OCH₂CH₂)_(j)—O—CONH—(C_(k)H_(2k))—  [Formula L¹-4],

—NH₂(CH₂)_(i)—(OCH₂CH₂)_(j)—O—(CH₂)_(k)—  [Formula L¹-5],

—NH₂(CH₂)_(i)—(OCH₂CH₂)_(j)—O—CONH—(CH₂)_(k)—  [Formula L¹-6],

—NH₂(C_(i)H_(2i))—(OCH₂CH₂)_(j)—O—(C_(k)H_(2k))—  [Formula L¹-7], or

—NH₂(C_(i)H_(2i))—(OCH₂CH₂)_(j)—O—CONH—(C_(k)H_(2k))—  [Formula L¹-8].

With respect to any relevant structural representation, such as FormulaL¹-1, L¹-2, 3, L¹-4, L¹-5, L¹-6, L¹-7, or L¹-8, i is 0, 1, 2, 3, or 4.In some embodiments, i is 2.

With respect to any relevant structural representation, such as FormulaL¹-1, L¹-2, L¹-3, L¹-4, L¹-5, L¹-6, L¹-7, or L¹-8, j is 0, 1, 2, 3, 4,or 5.

With respect to any relevant structural representation, such as FormulaL¹-1, L¹-2, L¹-3, L¹-4, L¹-5, L¹-6, L¹-7, or L¹-8, k is 0, 1, 2, 3, or4.

With respect to Formula L¹-1, L¹-2, L¹-3, L¹-4, L¹-5, L¹-6, L¹-7, orL¹-8, any H atom of an NH or an NH₂ moiety may be replaced with asubstituent, such as C₁₋₁₂ hydrocarbyl, C₁₋₆ hydrocarbyl, or C₁₋₃hydrocarbyl group, including phenyl, C₁₋₁₂ alkyl, C₁₋₆ alkyl, C₃₋₁₂cycloalkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₂₋₁₂ alkenyl, C₂₋₆ alkenyl,C₃₋₁₂ cycloalkenyl, C₃₋₆ cycloalkenyl, C₂₋₃ alkenyl, C₂₋₁₂ alkynyl, C₂₋₆alkynyl, C₈₋₁₂ cycloalkynyl, C₂₋₃ alkynyl, etc.

In some embodiments, H-L-H, HO-L-H, HO-L-OH, H₂N-L-H, or H₂N-L-NH₂, orHO-L-NH₂ is one or more of the following:

In some embodiments; a drug delivery system comprises one of thefollowing drug combinations; including salts; free acids; or free basedof the drugs; either covalently linked (such as by a linking group L,including groups represented by Formula L-1, L-2, L-3, L-4, L-5, L-6,L-7, or L-8 or not covalently linked: bimatoprost or bimatoprost acidand travoprost or travoprost acid; bimatoprost or bimatoprost acid andlatanoprost or latanoprost acid; bimatoprost or bimatoprost acid andlatanoprostene; bimatoprost or bimatoprost acid and tafluprost ortafluprost acid; bimatoprost or bimatoprost acid and timolol;bimatoprost or bimatoprost acid and betaxolol; bimatoprost orbimatoprost acid and levobunolol; bimatoprost or bimatoprost acid andmetipranolol; bimatoprost or bimatoprost acid and brimonidine;bimatoprost or bimatoprost acid and apraclonidine; bimatoprost orbimatoprost acid and brinzolamide; bimatoprost or bimatoprost acid andacetazolamide; bimatoprost or bimatoprost acid and dorzolamide;bimatoprost or bimatoprost acid and methazolamide; bimatoprost orbimatoprost acid and pilocarpine; bimatoprost or bimatoprost acid andcarbachol; bimatoprost or bimatoprost acid and netarsudil; bimatoprostor bimatoprost acid and angiopoietin-1; bimatoprost or bimatoprost acidand angiopoietin-2; bimatoprost or bimatoprost acid and angiopoietin-3;bimatoprost or bimatoprost acid and angiopoietin-4; bimatoprost orbimatoprost acid and CNTF; bimatoprost or bimatoprost acid and Peptide6; bimatoprost or bimatoprost acid and Peptide 21; bimatoprost orbimatoprost acid and recombinant CNTF; bimatoprost or bimatoprost acidand NGF; bimatoprost or bimatoprost acid and BDNF; bimatoprost orbimatoprost acid and GDNF; bimatoprost or bimatoprost acid and C-typeNatriuretic Peptide; bimatoprost or bimatoprost acid and natural C-typeNatriuretic Peptide; bimatoprost or bimatoprost acid and NatriureticPeptide Receptor-B; bimatoprost or bimatoprost acid and bicyclol;bimatoprost or bimatoprost acid and FLIP; bimatoprost or bimatoprostacid and MET12; bimatoprost or bimatoprost acid and compound 1 fromTable 1; bimatoprost or bimatoprost acid and compound 2 from Table 1;bimatoprost or bimatoprost acid and compound 3 from Table 1; bimatoprostor bimatoprost acid and compound 4 from Table 1; bimatoprost orbimatoprost acid and compound 5 from Table 1; bimatoprost or bimatoprostacid and compound 6 from Table 1; bimatoprost or bimatoprost acid andcompound 7 from Table 1; bimatoprost or bimatoprost acid and compound 8from Table 1; bimatoprost or bimatoprost acid and compound 9 from Table1; bimatoprost or bimatoprost acid and compound 10 from Table 1;bimatoprost or bimatoprost acid and compound 11 from Table 1;bimatoprost or bimatoprost acid and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4);bimatoprost or bimatoprost acid and FAIM; bimatoprost or bimatoprostacid and NOL3; bimatoprost or bimatoprost acid and DcR1; bimatoprost orbimatoprost acid and DcR2; bimatoprost or bimatoprost acid and DcR3;travoprost or travoprost acid and latanoprost or latanoprost acid;travoprost or travoprost acid and latanoprostene; travoprost ortravoprost acid and tafluprost or tafluprost acid; travoprost ortravoprost acid and timolol; travoprost or travoprost acid andbetaxolol; travoprost or travoprost acid and levobunolol; travoprost ortravoprost acid and metipranolol; travoprost or travoprost acid andbrimonidine; travoprost or travoprost acid and apraclonidine; travoprostor travoprost acid and brinzolamide; travoprost or travoprost acid andacetazolamide; travoprost or travoprost acid and dorzolamide; travoprostor travoprost acid and methazolamide; travoprost or travoprost acid andpilocarpine; travoprost or travoprost acid and carbachol; travoprost ortravoprost acid and netarsudil; travoprost or travoprost acid andangiopoietin-1; travoprost or travoprost acid and angiopoietin-2;travoprost or travoprost acid and angiopoietin-3; travoprost ortravoprost acid and a ngiopoietin-4; travoprost or travoprost acid andCNTF; travoprost or travoprost acid and Peptide 6; travoprost ortravoprost acid and Peptide 21; travoprost or travoprost acid andrecombinant CNTF; travoprost or travoprost acid and NGF; travoprost ortravoprost acid and BDNF; travoprost or travoprost acid and GDNF;travoprost or travoprost acid and C-type Natriuretic Peptide; travoprostor travoprost acid and natural C-type Natriuretic Peptide; travoprost ortravoprost acid and Natriuretic Peptide Receptor-B; travoprost ortravoprost acid and bicyclol; travoprost or travoprost acid and FLIP;travoprost or travoprost acid and MET12; travoprost or travoprost acidand compound 1 from Table 1; travoprost or travoprost acid and compound2 from Table 1; travoprost or travoprost acid and compound 3 from Table1; travoprost or travoprost acid and compound 4 from Table 1; travoprostor travoprost acid and compound 5 from Table 1; travoprost or travoprostacid and compound 6 from Table 1; travoprost or travoprost acid andcompound 7 from Table 1; travoprost or travoprost acid and compound 8from Table 1; travoprost or travoprost acid and compound 9 from Table 1;travoprost or travoprost acid and compound 10 from Table 1; travoprostor travoprost acid and compound 11 from Table 1; travoprost ortravoprost acid and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); travoprost ortravoprost acid and FAIM; travoprost or travoprost acid and NOL3;travoprost or travoprost acid and DcR1; travoprost or travoprost acidand DcR2; travoprost or travoprost acid and DcR3; latanoprost orlatanoprost acid and latanoprostene; latanoprost or latanoprost acid andtafluprost or tafluprost acid; latanoprost or latanoprost acid andtimolol; latanoprost or latanoprost acid and betaxolol; latanoprost orlatanoprost acid and levobunolol; latanoprost or latanoprost acid andmetipranolol; latanoprost or latanoprost acid and brimonidine;latanoprost or latanoprost acid and apraclonidine; latanoprost orlatanoprost acid and brinzolamide; latanoprost or latanoprost acid andacetazolamide; latanoprost or latanoprost acid and dorzolamide;latanoprost or latanoprost acid and methazolamide; latanoprost orlatanoprost acid and pilocarpine; latanoprost or latanoprost acid andcarbachol; latanoprost or latanoprost acid and netarsudil; latanoprostor latanoprost acid and angiopoietin-1; latanoprost or latanoprost acidand angiopoietin-2; latanoprost or latanoprost acid and angiopoietin-3;latanoprost or latanoprost acid and angiopoietin-4; latanoprost orlatanoprost acid and CNTF; latanoprost or latanoprost acid and Peptide6; latanoprost or latanoprost acid and Peptide 21; latanoprost orlatanoprost acid and recombinant CNTF; latanoprost or latanoprost acidand NGF; latanoprost or latanoprost acid and BDNF; latanoprost orlatanoprost acid and GDNF; latanoprost or latanoprost acid and C-typeNatriuretic Peptide; latanoprost or latanoprost acid and natural C-typeNatriuretic Peptide; latanoprost or latanoprost acid and NatriureticPeptide Receptor-B; latanoprost or latanoprost acid and bicyclol;latanoprost or latanoprost acid and FLIP; latanoprost or latanoprostacid and MET12; latanoprost or latanoprost acid and compound 1 fromTable 1; latanoprost or latanoprost acid and compound 2 from Table 1;latanoprost or latanoprost acid and compound 3 from Table 1; latanoprostor latanoprost acid and compound 4 from Table 1; latanoprost orlatanoprost acid and compound 5 from Table 1; latanoprost or latanoprostacid and compound 6 from Table 1; latanoprost or latanoprost acid andcompound 7 from Table 1; latanoprost or latanoprost acid and compound 8from Table 1; latanoprost or latanoprost acid and compound 9 from Table1; latanoprost or latanoprost acid and compound 10 from Table 1;latanoprost or latanoprost acid and compound 11 from Table 1;latanoprost or latanoprost acid and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4);latanoprost or latanoprost acid and FAIM; latanoprost or latanoprostacid and NOL3; latanoprost or latanoprost acid and DcR1; latanoprost orlatanoprost acid and DcR2; latanoprost or latanoprost acid and DcR3;latanoprostene and tafluprost or tafluprost acid; latanoprostene andtimolol; latanoprostene and betaxolol; latanoprostene and levobunolol;latanoprostene and metipranolol; latanoprostene and brimonidine;latanoprostene and apraclonidine; latanoprostene and brinzolamide;latanoprostene and acetazolamide; latanoprostene and dorzolamide;latanoprostene and methazolamide; latanoprostene and pilocarpine;latanoprostene and carbachol; latanoprostene and netarsudil;latanoprostene and angiopoietin-1; latanoprostene and a ngiopoietin-2;latanoprostene and angiopoietin-3; latanoprostene and angiopoietin-4;latanoprostene and CNTF; latanoprostene and Peptide 6; latanoprosteneand Peptide 21; latanoprostene and recombinant CNTF; latanoprostene andNGF; latanoprostene and BDNF; latanoprostene and GDNF; latanoprosteneand C-type Natriuretic Peptide; latanoprostene and natural C-typeNatriuretic Peptide; latanoprostene and Natriuretic Peptide Receptor-B;latanoprostene and bicyclol; latanoprostene and FLIP; latanoprostene andMET12; latanoprostene and compound 1 from Table 1; latanoprostene andcompound 2 from Table 1; latanoprostene and compound 3 from Table 1;latanoprostene and compound 4 from Table 1; latanoprostene and compound5 from Table 1; latanoprostene and compound 6 from Table 1;latanoprostene and compound 7 from Table 1; latanoprostene and compound8 from Table 1; latanoprostene and compound 9 from Table 1;latanoprostene and compound 10 from Table 1; latanoprostene and compound11 from Table 1; latanoprostene and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4);latanoprostene and FAIM; latanoprostene and NOL3; latanoprostene andDcR1; latanoprostene and DcR2; latanoprostene and DcR3; tafluprost ortafluprost acid and timolol; tafluprost or tafluprost acid andbetaxolol; tafluprost or tafluprost acid and levobunolol; tafluprost ortafluprost acid and metipranolol; tafluprost or tafluprost acid andbrimonidine; tafluprost or tafluprost acid and apraclonidine; tafluprostor tafluprost acid and brinzolamide; tafluprost or tafluprost acid andacetazolamide; tafluprost or tafluprost acid and dorzolamide; tafluprostor tafluprost acid and methazolamide; tafluprost or tafluprost acid andpilocarpine; tafluprost or tafluprost acid and carbachol; tafluprost ortafluprost acid and netarsudil; tafluprost or tafluprost acid andangiopoietin-1; tafluprost or tafluprost acid and angiopoietin-2;tafluprost or tafluprost acid and angiopoietin-3; tafluprost ortafluprost acid and angiopoietin-4; tafluprost or tafluprost acid andCNTF; tafluprost or tafluprost acid and Peptide 6; tafluprost ortafluprost acid and Peptide 21; tafluprost or tafluprost acid andrecombinant CNTF; tafluprost or tafluprost acid and NGF; tafluprost ortafluprost acid and BDNF; tafluprost or tafluprost acid and GDNF;tafluprost or tafluprost acid and C-type Natriuretic Peptide; tafluprostor tafluprost acid and natural C-type Natriuretic Peptide; tafluprost ortafluprost acid and Natriuretic Peptide Receptor-B; tafluprost ortafluprost acid and bicyclol; tafluprost or tafluprost acid and FLIP;tafluprost or tafluprost acid and MET12; tafluprost or tafluprost acidand compound 1 from Table 1; tafluprost or tafluprost acid and compound2 from Table 1; tafluprost or tafluprost acid and compound 3 from Table1; tafluprost or tafluprost acid and compound 4 from Table 1; tafluprostor tafluprost acid and compound 5 from Table 1; tafluprost or tafluprostacid and compound 6 from Table 1; tafluprost or tafluprost acid andcompound 7 from Table 1; tafluprost or tafluprost acid and compound 8from Table 1; tafluprost or tafluprost acid and compound 9 from Table 1;tafluprost or tafluprost acid and compound 10 from Table 1; tafluprostor tafluprost acid and compound 11 from Table 1; tafluprost ortafluprost acid and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); tafluprost ortafluprost acid and FAIM; tafluprost or tafluprost acid and NOL3;tafluprost or tafluprost acid and DcR1; tafluprost or tafluprost acidand DcR2; tafluprost or tafluprost acid and DcR3; timolol and betaxolol;timolol and levobunolol; timolol and metipranolol; timolol andbrimonidine; timolol and apraclonidine; timolol and brinzolamide;timolol and acetazolamide; timolol and dorzolamide; timolol andmethazolamide; timolol and pilocarpine; timolol and carbachol; timololand netarsudil; timolol and angiopoietin-1; timolol and angiopoietin-2;timolol and angiopoietin-3; timolol and angiopoietin-4; timolol andCNTF; timolol and Peptide 6; timolol and Peptide 21; timolol andrecombinant CNTF; timolol and NGF; timolol and BDNF; timolol and GDNF;timolol and C-type Natriuretic Peptide; timolol and natural C-typeNatriuretic Peptide; timolol and Natriuretic Peptide Receptor-B; timololand bicyclol; timolol and FLIP; timolol and MET12; timolol and compound1 from Table 1; timolol and compound 2 from Table 1; timolol andcompound 3 from Table 1; timolol and compound 4 from Table 1; timololand compound 5 from Table 1; timolol and compound 6 from Table 1;timolol and compound 7 from Table 1; timolol and compound 8 from Table1; timolol and compound 9 from Table 1; timolol and compound 10 fromTable 1; timolol and compound 11 from Table 1; timolol andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); timolol and FAIM; timolol and NOL3;timolol and DcR1; timolol and DcR2; timolol and DcR3; betaxolol andlevobunolol; betaxolol and metipranolol; betaxolol and brimonidine;betaxolol and apraclonidine; betaxolol and brinzolamide; betaxolol andacetazolamide; betaxolol and dorzolamide; betaxolol and methazolamide;betaxolol and pilocarpine; betaxolol and carbachol; betaxolol andnetarsudil; betaxolol and angiopoietin-1; betaxolol and angiopoietin-2;betaxolol and angiopoietin-3; betaxolol and angiopoietin-4; betaxololand CNTF; betaxolol and Peptide 6; betaxolol and Peptide 21; betaxololand recombinant CNTF; betaxolol and NGF; betaxolol and BDNF; betaxololand GDNF; betaxolol and C-type Natriuretic Peptide; betaxolol andnatural C-type Natriuretic Peptide; betaxolol and Natriuretic PeptideReceptor-B; betaxolol and bicyclol; betaxolol and FLIP; betaxolol andMET12; betaxolol and compound 1 from Table 1; betaxolol and compound 2from Table 1; betaxolol and compound 3 from Table 1; betaxolol andcompound 4 from Table 1; betaxolol and compound 5 from Table 1;betaxolol and compound 6 from Table 1; betaxolol and compound 7 fromTable 1; betaxolol and compound 8 from Table 1; betaxolol and compound 9from Table 1; betaxolol and compound 10 from Table 1; betaxolol andcompound 11 from Table 1; betaxolol and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO:4); betaxolol and FAIM; betaxolol and NOL3; betaxolol and DcR1;betaxolol and DcR2; betaxolol and DcR3; levobunolol and metipranolol;levobunolol and brimonidine; levobunolol and apraclonidine; levobunololand brinzolamide; levobunolol and acetazolamide; levobunolol anddorzolamide; levobunolol and methazolamide; levobunolol and pilocarpine;levobunolol and carbachol; levobunolol and netarsudil; levobunolol andangiopoietin-1; levobunolol and angiopoietin-2; levobunolol andangiopoietin-3; levobunolol and angiopoietin-4; levobunolol and CNTF;levobunolol and Peptide 6; levobunolol and Peptide 21; levobunolol andrecombinant CNTF; levobunolol and NGF; levobunolol and BDNF; levobunololand GDNF; levobunolol and C-type Natriuretic Peptide; levobunolol andnatural C-type Natriuretic Peptide; levobunolol and Natriuretic PeptideReceptor-B; levobunolol and bicyclol; levobunolol and FLIP; levobunololand MET12; levobunolol and compound 1 from Table 1; levobunolol andcompound 2 from Table 1; levobunolol and compound 3 from Table 1;levobunolol and compound 4 from Table 1; levobunolol and compound 5 fromTable 1; levobunolol and compound 6 from Table 1; levobunolol andcompound 7 from Table 1; levobunolol and compound 8 from Table 1;levobunolol and compound 9 from Table 1; levobunolol and compound 10from Table 1; levobunolol and compound 11 from Table 1; levobunolol andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); levobunolol and FAIM; levobunololand NOL3; levobunolol and DcR1; levobunolol and DcR2; levobunolol andDcR3; metipranolol and brimonidine; metipranolol and apraclonidine;metipranolol and brinzolamide; metipranolol and acetazolamide;metipranolol and dorzolamide; metipranolol and methazolamide;metipranolol and pilocarpine; metipranolol and carbachol; metipranololand netarsudil; metipranolol and angiopoietin-1; metipranolol andangiopoietin-2; metipranolol and angiopoietin-3; metipranolol andangiopoietin-4; metipranolol and CNTF; metipranolol and Peptide 6;metipranolol and Peptide 21; metipranolol and recombinant CNTF;metipranolol and NGF; metipranolol and BDNF; metipranolol and GDNF;metipranolol and C-type Natriuretic Peptide; metipranolol and naturalC-type Natriuretic Peptide; metipranolol and Natriuretic PeptideReceptor-B; metipranolol and bicyclol; metipranolol and FLIP;metipranolol and MET12; metipranolol and compound 1 from Table 1;metipranolol and compound 2 from Table 1; metipranolol and compound 3from Table 1; metipranolol and compound 4 from Table 1; metipranolol andcompound 5 from Table 1; metipranolol and compound 6 from Table 1;metipranolol and compound 7 from Table 1; metipranolol and compound 8from Table 1; metipranolol and compound 9 from Table 1; metipranolol andcompound 10 from Table 1; metipranolol and compound 11 from Table 1;metipranolol and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); metipranolol andFAIM; metipranolol and NOL3; metipranolol and DcR1; metipranolol andDcR2; metipranolol and DcR3; brimonidine and apraclonidine; brimonidineand brinzolamide; brimonidine and acetazolamide; brimonidine anddorzolamide; brimonidine and methazolamide; brimonidine and pilocarpine;brimonidine and carbachol; brimonidine and netarsudil; brimonidine andangiopoietin-1; brimonidine and angiopoietin-2; brimonidine andangiopoietin-3; brimonidine and angiopoietin-4; brimonidine and CNTF;brimonidine and Peptide 6; brimonidine and Peptide 21; brimonidine andrecombinant CNTF; brimonidine and NGF; brimonidine and BDNF; brimonidineand GDNF; brimonidine and C-type Natriuretic Peptide; brimonidine andnatural C-type Natriuretic Peptide; brimonidine and Natriuretic PeptideReceptor-B; brimonidine and bicyclol; brimonidine and FLIP; brimonidineand MET12; brimonidine and compound 1 from Table 1; brimonidine andcompound 2 from Table 1; brimonidine and compound 3 from Table 1;brimonidine and compound 4 from Table 1; brimonidine and compound 5 fromTable 1; brimonidine and compound 6 from Table 1; brimonidine andcompound 7 from Table 1; brimonidine and compound 8 from Table 1;brimonidine and compound 9 from Table 1; brimonidine and compound 10from Table 1; brimonidine and compound 11 from Table 1; brimonidine andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); brimonidine and FAIM; brimonidineand NOL3; brimonidine and DcR1; brimonidine and DcR2; brimonidine andDcR3; apraclonidine and brinzolamide; apraclonidine and acetazolamide;apraclonidine and dorzolamide; apraclonidine and methazolamide;apraclonidine and pilocarpine; apraclonidine and carbachol;apraclonidine and netarsudil; apraclonidine and angiopoietin-1;apraclonidine and angiopoietin-2; apraclonidine and angiopoietin-3;apraclonidine and angiopoietin-4; apraclonidine and CNTF; apraclonidineand Peptide 6; apraclonidine and Peptide 21; apraclonidine andrecombinant CNTF; apraclonidine and NGF; apraclonidine and BDNF;apraclonidine and GDNF; apraclonidine and C-type Natriuretic Peptide;apraclonidine and natural C-type Natriuretic Peptide; apraclonidine andNatriuretic Peptide Receptor-B; apraclonidine and bicyclol;apraclonidine and FLIP; apraclonidine and MET12; apraclonidine andcompound 1 from Table 1; apraclonidine and compound 2 from Table 1;apraclonidine and compound 3 from Table 1; apraclonidine and compound 4from Table 1; apraclonidine and compound 5 from Table 1; apraclonidineand compound 6 from Table 1; apraclonidine and compound 7 from Table 1;apraclonidine and compound 8 from Table 1; apraclonidine and compound 9from Table 1; apraclonidine and compound 10 from Table 1; apraclonidineand compound 11 from Table 1; apraclonidine and H⁶⁰HIYLGATNYIY⁷¹-NH₂(SEQ ID NO: 4); apraclonidine and FAIM; apraclonidine and NOL3;apraclonidine and DcR1; apraclonidine and DcR2; apraclonidine and DcR3;brinzolamide and acetazolamide; brinzolamide and dorzolamide;brinzolamide and methazolamide; brinzolamide and pilocarpine;brinzolamide and carbachol; brinzolamide and netarsudil; brinzolamideand angiopoietin-1; brinzolamide and angiopoietin-2; brinzolamide andangiopoietin-3; brinzolamide and angiopoietin-4; brinzolamide and CNTF;brinzolamide and Peptide 6; brinzolamide and Peptide 21; brinzolamideand recombinant CNTF; brinzolamide and NGF; brinzolamide and BDNF;brinzolamide and GDNF; brinzolamide and C-type Natriuretic Peptide;brinzolamide and natural C-type Natriuretic Peptide; brinzolamide andNatriuretic Peptide Receptor-B; brinzolamide and bicyclol; brinzolamideand FLIP; brinzolamide and MET12; brinzolamide and compound 1 from Table1; brinzolamide and compound 2 from Table 1; brinzolamide and compound 3from Table 1; brinzolamide and compound 4 from Table 1; brinzolamide andcompound 5 from Table 1; brinzolamide and compound 6 from Table 1;brinzolamide and compound 7 from Table 1; brinzolamide and compound 8from Table 1; brinzolamide and compound 9 from Table 1; brinzolamide andcompound 10 from Table 1; brinzolamide and compound 11 from Table 1;brinzolamide and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); brinzolamide andFAIM; brinzolamide and NOL3; brinzolamide and DcR1; brinzolamide andDcR2; brinzolamide and DcR3; acetazolamide and dorzolamide;acetazolamide and methazolamide; acetazolamide and pilocarpine;acetazolamide and carbachol; acetazolamide and netarsudil; acetazolamideand angiopoietin-1; acetazolamide and a ngiopoietin-2; acetazolamide andangiopoietin-3; acetazolamide and angiopoietin-4; acetazolamide andCNTF; acetazolamide and Peptide 6; acetazolamide and Peptide 21;acetazolamide and recombinant CNTF; acetazolamide and NGF; acetazolamideand BDNF; acetazolamide and GDNF; acetazolamide and C-type NatriureticPeptide; acetazolamide and natural C-type Natriuretic Peptide;acetazolamide and Natriuretic Peptide Receptor-B; acetazolamide andbicyclol; acetazolamide and FLIP; acetazolamide and MET12; acetazolamideand compound 1 from Table 1; acetazolamide and compound 2 from Table 1;acetazolamide and compound 3 from Table 1; acetazolamide and compound 4from Table 1; acetazolamide and compound 5 from Table 1; acetazolamideand compound 6 from Table 1; acetazolamide and compound 7 from Table 1;acetazolamide and compound 8 from Table 1; acetazolamide and compound 9from Table 1; acetazolamide and compound 10 from Table 1; acetazolamideand compound 11 from Table 1; acetazolamide and H⁶⁰HIYLGATNYIY⁷¹-NH₂(SEQ ID NO: 4); acetazolamide and FAIM; acetazolamide and NOL3;acetazolamide and DcR1; acetazolamide and DcR2; acetazolamide and DcR3;dorzolamide and methazolamide; dorzolamide and pilocarpine; dorzolamideand carbachol; dorzolamide and netarsudil; dorzolamide andangiopoietin-1; dorzolamide and angiopoietin-2; dorzolamide andangiopoietin-3; dorzolamide and angiopoietin-4; dorzolamide and CNTF;dorzolamide and Peptide 6; dorzolamide and Peptide 21; dorzolamide andrecombinant CNTF; dorzolamide and NGF; dorzolamide and BDNF; dorzolamideand GDNF; dorzolamide and C-type Natriuretic Peptide; dorzolamide andnatural C-type Natriuretic Peptide; dorzolamide and Natriuretic PeptideReceptor-B; dorzolamide and bicyclol; dorzolamide and FLIP; dorzolamideand MET12; dorzolamide and compound 1 from Table 1; dorzolamide andcompound 2 from Table 1; dorzolamide and compound 3 from Table 1;dorzolamide and compound 4 from Table 1; dorzolamide and compound 5 fromTable 1; dorzolamide and compound 6 from Table 1; dorzolamide andcompound 7 from Table 1; dorzolamide and compound 8 from Table 1;dorzolamide and compound 9 from Table 1; dorzolamide and compound 10from Table 1; dorzolamide and compound 11 from Table 1; dorzolamide andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); dorzolamide and FAIM; dorzolamideand NOL3; dorzolamide and DcR1; dorzolamide and DcR2; dorzolamide andDcR3; methazolamide and pilocarpine; methazolamide and carbachol;methazolamide and netarsudil; methazolamide and angiopoietin-1;methazolamide and angiopoietin-2; methazolamide and angiopoietin-3;methazolamide and angiopoietin-4; methazolamide and CNTF; methazolamideand Peptide 6; methazolamide and Peptide 21; methazolamide andrecombinant CNTF; methazolamide and NGF; methazolamide and BDNF;methazolamide and GDNF; methazolamide and C-type Natriuretic Peptide;methazolamide and natural C-type Natriuretic Peptide; PeptideReceptor-B; methazolamide and Natriuretic Peptide Receptor-B;methazolamide and bicyclol; methazolamide and FLIP; methazolamide andMET12; methazolamide and compound 1 from Table 1; methazolamide andcompound 2 from Table 1; methazolamide and compound 3 from Table 1;methazolamide and compound 4 from Table 1; methazolamide and compound 5from Table 1; methazolamide and compound 6 from Table 1; methazolamideand compound 7 from Table 1; methazolamide and compound 8 from Table 1;methazolamide and compound 9 from Table 1; methazolamide and compound 10from Table 1; methazolamide and compound 11 from Table 1; methazolamideand H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); methazolamide and FAIM;methazolamide and NOL3; methazolamide and DcR1; methazolamide and DcR2;methazolamide and DcR3; pilocarpine and carbachol; pilocarpine andnetarsudil; pilocarpine and angiopoietin-1; pilocarpine andangiopoietin-2; pilocarpine and angiopoietin-3; pilocarpine andangiopoietin-4; pilocarpine and CNTF; pilocarpine and Peptide 6;pilocarpine and Peptide 21; pilocarpine and recombinant CNTF;pilocarpine and NGF; pilocarpine and BDNF; pilocarpine and GDNF;pilocarpine and C-type Natriuretic Peptide; pilocarpine and naturalC-type Natriuretic Peptide; pilocarpine and Natriuretic PeptideReceptor-B; pilocarpine and bicyclol; pilocarpine and FLIP; pilocarpineand MET12; pilocarpine and compound 1 from Table 1; pilocarpine andcompound 2 from Table 1; pilocarpine and compound 3 from Table 1;pilocarpine and compound 4 from Table 1; pilocarpine and compound 5 fromTable 1; pilocarpine and compound 6 from Table 1; pilocarpine andcompound 7 from Table 1; pilocarpine and compound 8 from Table 1;pilocarpine and compound 9 from Table 1; pilocarpine and compound 10from Table 1; pilocarpine and compound 11 from Table 1; pilocarpine andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); pilocarpine and FAIM; pilocarpineand NOL3; pilocarpine and DcR1; pilocarpine and DcR2; pilocarpine andDcR3; carbachol and netarsudil; carbachol and angiopoietin-1; carbacholand angiopoietin-2; carbachol and angiopoietin-3; carbachol andangiopoietin-4; carbachol and CNTF; carbachol and Peptide 6; carbacholand Peptide 21; carbachol and recombinant CNTF; carbachol and NGF;carbachol and BDNF; carbachol and GDNF; carbachol and C-type NatriureticPeptide; carbachol and natural C-type Natriuretic Peptide; carbachol andNatriuretic Peptide Receptor-B; carbachol and bicyclol; carbachol andFLIP; carbachol and MET12; carbachol and compound 1 from Table 1;carbachol and compound 2 from Table 1; carbachol and compound 3 fromTable 1; carbachol and compound 4 from Table 1; carbachol and compound 5from Table 1; carbachol and compound 6 from Table 1; carbachol andcompound 7 from Table 1; carbachol and compound 8 from Table 1;carbachol and compound 9 from Table 1; carbachol and compound 10 fromTable 1; carbachol and compound 11 from Table 1; carbachol andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); carbachol and FAIM; carbachol andNOL3; carbachol and DcR1; carbachol and DcR2; carbachol and DcR3;netarsudil and angiopoietin-1; netarsudil and angiopoietin-2; netarsudiland angiopoietin-3; netarsudil and angiopoietin-4; netarsudil and CNTF;netarsudil and Peptide 6; netarsudil and Peptide 21; netarsudil andrecombinant CNTF; netarsudil and NGF; netarsudil and BDNF; netarsudiland GDNF; netarsudil and C-type Natriuretic Peptide; netarsudil andnatural C-type Natriuretic Peptide; netarsudil and Natriuretic PeptideReceptor-B; netarsudil and bicyclol; netarsudil and FLIP; netarsudil andMET12; netarsudil and compound 1 from Table 1; netarsudil and compound 2from Table 1; netarsudil and compound 3 from Table 1; netarsudil andcompound 4 from Table 1; netarsudil and compound 5 from Table 1;netarsudil and compound 6 from Table 1; netarsudil and compound 7 fromTable 1; netarsudil and compound 8 from Table 1; netarsudil and compound9 from Table 1; netarsudil and compound 10 from Table 1; netarsudil andcompound 11 from Table 1; netarsudil and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ IDNO: 4); netarsudil and FAIM; netarsudil and NOL3; netarsudil and DcR1;netarsudil and DcR2; netarsudil and DcR3; angiopoietin-1 andangiopoietin-2; angiopoietin-1 and angiopoietin-3; angiopoietin-1 andangiopoietin-4; angiopoietin-1 and CNTF; angiopoietin-1 and Peptide 6;angiopoietin-1 and Peptide 21; angiopoietin-1 and recombinant CNTF;angiopoietin-1 and NGF; angiopoietin-1 and BDNF; angiopoietin-1 andGDNF; angiopoietin-1 and C-type Natriuretic Peptide; angiopoietin-1 andnatural C-type Natriuretic Peptide; angiopoietin-1 and NatriureticPeptide Receptor-B; angiopoietin-1 and bicyclol; angiopoietin-1 andFLIP; angiopoietin-1 and MET12; angiopoietin-1 and compound 1 from Table1; angiopoietin-1 and compound 2 from Table 1; angiopoietin-1 andcompound 3 from Table 1; angiopoietin-1 and compound 4 from Table 1;angiopoietin-1 and compound 5 from Table 1; a ngiopoietin-1 and compound6 from Table 1; a ngiopoietin-1 and compound 7 from Table 1;angiopoietin-1 and compound 8 from Table 1; angiopoietin-1 and compound9 from Table 1; angiopoietin-1 and compound 10 from Table 1;angiopoietin-1 and compound 11 from Table 1; angiopoietin-1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); angiopoietin-1 and FAIM;angiopoietin-1 and NOL3; angiopoietin-1 and DcR1; angiopoietin-1 andDcR2; angiopoietin-1 and DcR3; angiopoietin-2 and angiopoietin-3;angiopoietin-2 and angiopoietin-4; angiopoietin-2 and CNTF;angiopoietin-2 and Peptide 6; angiopoietin-2 and Peptide 21;angiopoietin-2 and recombinant CNTF; angiopoietin-2 and NGF;angiopoietin-2 and BDNF; angiopoietin-2 and GDNF; angiopoietin-2 andC-type Natriuretic Peptide; angiopoietin-2 and natural C-typeNatriuretic Peptide; angiopoietin-2 and Natriuretic Peptide Receptor-B;angiopoietin-2 and bicyclol; angiopoietin-2 and FLIP; angiopoietin-2 andMET12; angiopoietin-2 and compound 1 from Table 1; angiopoietin-2 andcompound 2 from Table 1; angiopoietin-2 and compound 3 from Table 1;angiopoietin-2 and compound 4 from Table 1; angiopoietin-2 and compound5 from Table 1; angiopoietin-2 and compound 6 from Table 1;angiopoietin-2 and compound 7 from Table 1; angiopoietin-2 and compound8 from Table 1; angiopoietin-2 and compound 9 from Table 1;angiopoietin-2 and compound 10 from Table 1; angiopoietin-2 and compound11 from Table 1; angiopoietin-2 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4);angiopoietin-2 and FAIM; angiopoietin-2 and NOL3; angiopoietin-2 andDcR1; angiopoietin-2 and DcR2; angiopoietin-2 and DcR3; angiopoietin-3and angiopoietin-4; angiopoietin-3 and CNTF; angiopoietin-3 and Peptide6; angiopoietin-3 and Peptide 21; angiopoietin-3 and recombinant CNTF;angiopoietin-3 and NGF; angiopoietin-3 and BDNF; angiopoietin-3 andGDNF; angiopoietin-3 and C-type Natriuretic Peptide; angiopoietin-3 andnatural C-type Natriuretic Peptide; angiopoietin-3 and NatriureticPeptide Receptor-B; angiopoietin-3 and bicyclol; angiopoietin-3 andFLIP; angiopoietin-3 and MET12; angiopoietin-3 and compound 1 from Table1; angiopoietin-3 and compound 2 from Table 1; angiopoietin-3 andcompound 3 from Table 1; angiopoietin-3 and compound 4 from Table 1;angiopoietin-3 and compound 5 from Table 1; angiopoietin-3 and compound6 from Table 1; angiopoietin-3 and compound 7 from Table 1;angiopoietin-3 and compound 8 from Table 1; angiopoietin-3 and compound9 from Table 1; a ngiopoietin-3 and compound 10 from Table 1;angiopoietin-3 and compound 11 from Table 1; angiopoietin-3 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); angiopoietin-3 and FAIM;angiopoietin-3 and NOL3; angiopoietin-3 and DcR1; angiopoietin-3 andDcR2; angiopoietin-3 and DcR3; angiopoietin-4 and CNTF; angiopoietin-4and Peptide 6; angiopoietin-4 and Peptide 21; angiopoietin-4 andrecombinant CNTF; angiopoietin-4 and NGF; angiopoietin-4 and BDNF;angiopoietin-4 and GDNF; angiopoietin-4 and C-type Natriuretic Peptide;angiopoietin-4 and natural C-type Natriuretic Peptide; angiopoietin-4and Natriuretic Peptide Receptor-B; angiopoietin-4 and bicyclol;angiopoietin-4 and FLIP; angiopoietin-4 and MET12; angiopoietin-4 andcompound 1 from Table 1; angiopoietin-4 and compound 2 from Table 1;angiopoietin-4 and compound 3 from Table 1; angiopoietin-4 and compound4 from Table 1; angiopoietin-4 and compound 5 from Table 1;angiopoietin-4 and compound 6 from Table 1; angiopoietin-4 and compound7 from Table 1; angiopoietin-4 and compound 8 from Table 1;angiopoietin-4 and compound 9 from Table 1; angiopoietin-4 and compound10 from Table 1; angiopoietin-4 and compound 11 from Table 1;angiopoietin-4 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); angiopoietin-4and FAIM; angiopoietin-4 and NOL3; angiopoietin-4 and DcR1;angiopoietin-4 and DcR2; angiopoietin-4 and DcR3; CNTF and Peptide 6;CNTF and Peptide 21; CNTF and recombinant CNTF; CNTF and NGF; CNTF andBDNF; CNTF and GDNF; CNTF and C-type Natriuretic Peptide; CNTF andnatural C-type Natriuretic Peptide; CNTF and Natriuretic PeptideReceptor-B; CNTF and bicyclol; CNTF and FLIP; CNTF and MET12; CNTF andcompound 1 from Table 1; CNTF and compound 2 from Table 1; CNTF andcompound 3 from Table 1; CNTF and compound 4 from Table 1; CNTF andcompound 5 from Table 1; CNTF and compound 6 from Table 1; CNTF andcompound 7 from Table 1; CNTF and compound 8 from Table 1; CNTF andcompound 9 from Table 1; CNTF and compound 10 from Table 1; CNTF andcompound 11 from Table 1; CNTF and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4);CNTF and FAIM; CNTF and NOL3; CNTF and DcR1; CNTF and DcR2; CNTF andDcR3; Peptide 6 and Peptide 21; Peptide 6 and recombinant Peptide 6;Peptide 6 and NGF; Peptide 6 and BDNF; Peptide 6 and GDNF; Peptide 6 andC-type Natriuretic Peptide; Peptide 6 and natural C-type NatriureticPeptide; Peptide 6 and Natriuretic Peptide Receptor-B; Peptide 6 andbicyclol; Peptide 6 and FLIP; Peptide 6 and MET12; Peptide 6 andcompound 1 from Table 1; Peptide 6 and compound 2 from Table 1; Peptide6 and compound 3 from Table 1; Peptide 6 and compound 4 from Table 1;Peptide 6 and compound 5 from Table 1; Peptide 6 and compound 6 fromTable 1; Peptide 6 and compound 7 from Table 1; Peptide 6 and compound 8from Table 1; Peptide 6 and compound 9 from Table 1; Peptide 6 andcompound 10 from Table 1; Peptide 6 and compound 11 from Table 1;Peptide 6 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); Peptide 6 and FAIM;Peptide 6 and NOL3; Peptide 6 and DcR1; Peptide 6 and DcR2; Peptide 6and DcR3; Peptide 21 and recombinant Peptide 21; Peptide 21 and NGF;Peptide 21 and BDNF; Peptide 21 and GDNF; Peptide 21 and C-typeNatriuretic Peptide; Peptide 21 and natural C-type Natriuretic Peptide;Peptide 21 and Natriuretic Peptide Receptor-B; Peptide 21 and bicyclol;Peptide 21 and FLIP; Peptide 21 and MET12; Peptide 21 and compound 1from Table 1; Peptide 21 and compound 2 from Table 1; Peptide 21 andcompound 3 from Table 1; Peptide 21 and compound 4 from Table 1; Peptide21 and compound 5 from Table 1; Peptide 21 and compound 6 from Table 1;Peptide 21 and compound 7 from Table 1; Peptide 21 and compound 8 fromTable 1; Peptide 21 and compound 9 from Table 1; Peptide 21 and compound10 from Table 1; Peptide 21 and compound 11 from Table 1; Peptide 21 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); Peptide 21 and FAIM; Peptide 21 andNOL3; Peptide 21 and DcR1; Peptide 21 and DcR2; Peptide 21 and DcR3;recombinant Peptide 21 and NGF; recombinant Peptide 21 and BDNF;recombinant Peptide 21 and GDNF; recombinant Peptide 21 and C-typeNatriuretic Peptide; recombinant Peptide 21 and natural C-typeNatriuretic Peptide; recombinant Peptide 21 and Natriuretic PeptideReceptor-B; recombinant Peptide 21 and bicyclol; recombinant Peptide 21and FLIP; recombinant Peptide 21 and MET12; recombinant Peptide 21 andcompound 1 from Table 1; recombinant Peptide 21 and compound 2 fromTable 1; recombinant Peptide 21 and compound 3 from Table 1; recombinantPeptide 21 and compound 4 from Table 1; recombinant Peptide 21 andcompound 5 from Table 1; recombinant Peptide 21 and compound 6 fromTable 1; recombinant Peptide 21 and compound 7 from Table 1; recombinantPeptide 21 and compound 8 from Table 1; recombinant Peptide 21 andcompound 9 from Table 1; recombinant Peptide 21 and compound 10 fromTable 1; recombinant Peptide 21 and compound 11 from Table 1;recombinant Peptide 21 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4);recombinant Peptide 21 and FAIM; recombinant Peptide 21 and NOL3;recombinant Peptide 21 and DcR1; recombinant Peptide 21 and DcR2;recombinant Peptide 21 and DcR3; NGF and BDNF; NGF and GDNF; NGF andC-type Natriuretic Peptide; NGF and natural C-type Natriuretic Peptide;NGF and Natriuretic Peptide Receptor-B; NGF and bicyclol; NGF and FLIP;NGF and MET12; NGF and compound 1 from Table 1; NGF and compound 2 fromTable 1; NGF and compound 3 from Table 1; NGF and compound 4 from Table1; NGF and compound 5 from Table 1; NGF and compound 6 from Table 1; NGFand compound 7 from Table 1; NGF and compound 8 from Table 1; NGF andcompound 9 from Table 1; NGF and compound 10 from Table 1; NGF andcompound 11 from Table 1; NGF and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4);NGF and FAIM; NGF and NOL3; NGF and DcR1; NGF and DcR2; NGF and DcR3;BDNF and GDNF; BDNF and C-type Natriuretic Peptide; BDNF and naturalC-type Natriuretic Peptide; BDNF and Natriuretic Peptide Receptor-B;BDNF and bicyclol; BDNF and FLIP; BDNF and MET12; BDNF and compound 1from Table 1; BDNF and compound 2 from Table 1; BDNF and compound 3 fromTable 1; BDNF and compound 4 from Table 1; BDNF and compound 5 fromTable 1; BDNF and compound 6 from Table 1; BDNF and compound 7 fromTable 1; BDNF and compound 8 from Table 1; BDNF and compound 9 fromTable 1; BDNF and compound 10 from Table 1; BDNF and compound 11 fromTable 1; BDNF and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); BDNF and FAIM;BDNF and NOL3; BDNF and DcR1; BDNF and DcR2; BDNF and DcR3; GDNF andC-type Natriuretic Peptide; GDNF and natural C-type Natriuretic Peptide;GDNF and Natriuretic Peptide Receptor-B; GDNF and bicyclol; GDNF andFLIP; GDNF and MET12; GDNF and compound 1 from Table 1; GDNF andcompound 2 from Table 1; GDNF and compound 3 from Table 1; GDNF andcompound 4 from Table 1; GDNF and compound 5 from Table 1; GDNF andcompound 6 from Table 1; GDNF and compound 7 from Table 1; GDNF andcompound 8 from Table 1; GDNF and compound 9 from Table 1; GDNF andcompound 10 from Table 1; GDNF and compound 11 from Table 1; GDNF andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); GDNF and FAIM; GDNF and NOL3; GDNFand DcR1; GDNF and DcR2; GDNF and DcR3; C-type Natriuretic Peptide andnatural C-type Natriuretic Peptide; C-type Natriuretic Peptide andNatriuretic Peptide Receptor-B; C-type Natriuretic Peptide and bicyclol;C-type Natriuretic Peptide and FLIP; C-type Natriuretic Peptide andMET12; C-type Natriuretic Peptide and compound 1 from Table 1; C-typeNatriuretic Peptide and compound 2 from Table 1; C-type NatriureticPeptide and compound 3 from Table 1; C-type Natriuretic Peptide andcompound 4 from Table 1; C-type Natriuretic Peptide and compound 5 fromTable 1; C-type Natriuretic Peptide and compound 6 from Table 1; C-typeNatriuretic Peptide and compound 7 from Table 1; C-type NatriureticPeptide and compound 8 from Table 1; C-type Natriuretic Peptide andcompound 9 from Table 1; C-type Natriuretic Peptide and compound 10 fromTable 1; C-type Natriuretic Peptide and compound 11 from Table 1; C-typeNatriuretic Peptide and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); C-typeNatriuretic Peptide and FAIM; C-type Natriuretic Peptide and NOL3;C-type Natriuretic Peptide and DcR1; C-type Natriuretic Peptide andDcR2; C-type Natriuretic Peptide and DcR3; natural C-type NatriureticPeptide and Natriuretic Peptide Receptor-B; natural C-type NatriureticPeptide and bicyclol; natural C-type Natriuretic Peptide and FLIP;natural C-type Natriuretic Peptide and MET12; natural C-type NatriureticPeptide and compound 1 from Table 1; natural C-type Natriuretic Peptideand compound 2 from Table 1; natural C-type Natriuretic Peptide andcompound 3 from Table 1; natural C-type Natriuretic Peptide and compound4 from Table 1; natural C-type Natriuretic Peptide and compound 5 fromTable 1; natural C-type Natriuretic Peptide and compound 6 from Table 1;natural C-type Natriuretic Peptide and compound 7 from Table 1; naturalC-type Natriuretic Peptide and compound 8 from Table 1; natural C-typeNatriuretic Peptide and compound 9 from Table 1; natural C-typeNatriuretic Peptide and compound 10 from Table 1; natural C-typeNatriuretic Peptide and compound 11 from Table 1; natural C-typeNatriuretic Peptide and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); naturalC-type Natriuretic Peptide and FAIM; natural C-type Natriuretic Peptideand NOL3; natural C-type Natriuretic Peptide and DcR1; natural C-typeNatriuretic Peptide and DcR2; natural C-type Natriuretic Peptide andDcR3; Natriuretic Peptide Receptor-B and bicyclol; Natriuretic PeptideReceptor-B and FLIP; Natriuretic Peptide Receptor-B and MET12;Natriuretic Peptide Receptor-B and compound 1 from Table 1; NatriureticPeptide Receptor-B and compound 2 from Table 1; Natriuretic PeptideReceptor-B and compound 3 from Table 1; Natriuretic Peptide Receptor-Band compound 4 from Table 1; Natriuretic Peptide Receptor-B and compound5 from Table 1; Natriuretic Peptide Receptor-B and compound 6 from Table1; Natriuretic Peptide Receptor-B and compound 7 from Table 1;Natriuretic Peptide Receptor-B and compound 8 from Table 1; NatriureticPeptide Receptor-B and compound 9 from Table 1; Natriuretic PeptideReceptor-B and compound 10 from Table 1; Natriuretic Peptide Receptor-Band compound 11 from Table 1; Natriuretic Peptide Receptor-B andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); Natriuretic Peptide Receptor-B andFAIM; Natriuretic Peptide Receptor-B and NOL3; Natriuretic PeptideReceptor-B and DcR1; Natriuretic Peptide Receptor-B and DcR2;Natriuretic Peptide Receptor-B and DcR3; bicyclol and FLIP; bicyclol andMET12; bicyclol and compound 1 from Table 1; bicyclol and compound 2from Table 1; bicyclol and compound 3 from Table 1; bicyclol andcompound 4 from Table 1; bicyclol and compound 5 from Table 1; bicycloland compound 6 from Table 1; bicyclol and compound 7 from Table 1;bicyclol and compound 8 from Table 1; bicyclol and compound 9 from Table1; bicyclol and compound 10 from Table 1; bicyclol and compound 11 fromTable 1; bicyclol and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); bicyclol andFAIM; bicyclol and NOL3; bicyclol and DcR1; bicyclol and DcR2; bicycloland DcR3; FLIP and MET12; FLIP and compound 1 from Table 1; FLIP andcompound 2 from Table 1; FLIP and compound 3 from Table 1; FLIP andcompound 4 from Table 1; FLIP and compound 5 from Table 1; FLIP andcompound 6 from Table 1; FLIP and compound 7 from Table 1; FLIP andcompound 8 from Table 1; FLIP and compound 9 from Table 1; FLIP andcompound 10 from Table 1; FLIP and compound 11 from Table 1; FLIP andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); FLIP and FAIM; FLIP and NOL3; FLIPand DcR1; FLIP and DcR2; FLIP and DcR3; MET12 and compound 1 from Table1; MET12 and compound 2 from Table 1; MET12 and compound 3 from Table 1;MET12 and compound 4 from Table 1; MET12 and compound 5 from Table 1;MET12 and compound 6 from Table 1; MET12 and compound 7 from Table 1;MET12 and compound 8 from Table 1; MET12 and compound 9 from Table 1;MET12 and compound 10 from Table 1; MET12 and compound 11 from Table 1;MET12 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); MET12 and FAIM; MET12 andNOL3; MET12 and DcR1; MET12 and DcR2; MET12 and DcR3; compound 1 fromTable 1 and compound 2 from Table 1; compound 1 from Table 1 andcompound 3 from Table 1; compound 1 from Table 1 and compound 4 fromTable 1; compound 1 from Table 1 and compound 5 from Table 1; compound 1from Table 1 and compound 6 from Table 1; compound 1 from Table 1 andcompound 7 from Table 1; compound 1 from Table 1 and compound 8 fromTable 1; compound 1 from Table 1 and compound 9 from Table 1; compound 1from Table 1 and compound 10 from Table 1; compound 1 from Table 1 andcompound 11 from Table 1; compound 1 from Table 1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 1 from Table 1 and FAIM;compound 1 from Table 1 and NOL3; compound 1 from Table 1 and DcR1;compound 1 from Table 1 and DcR2; compound 1 from Table 1 and DcR3;compound 2 from Table 1 and compound 3 from Table 1; compound 2 fromTable 1 and compound 4 from Table 1; compound 2 from Table 1 andcompound 5 from Table 1; compound 2 from Table 1 and compound 6 fromTable 1; compound 2 from Table 1 and compound 7 from Table 1; compound 2from Table 1 and compound 8 from Table 1; compound 2 from Table 1 andcompound 9 from Table 1; compound 2 from Table 1 and compound 10 fromTable 1; compound 2 from Table 1 and compound 11 from Table 1; compound2 from Table 1 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 2 fromTable 1 and FAIM; compound 2 from Table 1 and NOL3; compound 2 fromTable 1 and DcR1; compound 2 from Table 1 and DcR2; compound 2 fromTable 1 and DcR3; compound 3 from Table 1 and compound 4 from Table 1;compound 3 from Table 1 and compound 5 from Table 1; compound 3 fromTable 1 and compound 6 from Table 1; compound 3 from Table 1 andcompound 7 from Table 1; compound 3 from Table 1 and compound 8 fromTable 1; compound 3 from Table 1 and compound 9 from Table 1; compound 3from Table 1 and compound 10 from Table 1; compound 3 from Table 1 andcompound 11 from Table 1; compound 3 from Table 1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 3 from Table 1 and FAIM;compound 3 from Table 1 and NOL3; compound 3 from Table 1 and DcR1;compound 3 from Table 1 and DcR2; compound 3 from Table 1 and DcR3;compound 4 from Table 1 and compound 5 from Table 1; compound 4 fromTable 1 and compound 6 from Table 1; compound 4 from Table 1 andcompound 7 from Table 1; compound 4 from Table 1 and compound 8 fromTable 1; compound 4 from Table 1 and compound 9 from Table 1; compound 4from Table 1 and compound 10 from Table 1; compound 4 from Table 1 andcompound 11 from Table 1; compound 4 from Table 1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 4 from Table 1 and FAIM;compound 4 from Table 1 and NOL3; compound 4 from Table 1 and DcR1;compound 4 from Table 1 and DcR2; compound 4 from Table 1 and DcR3;compound 5 from Table 1 and compound 6 from Table 1; compound 5 fromTable 1 and compound 7 from Table 1; compound 5 from Table 1 andcompound 8 from Table 1; compound 5 from Table 1 and compound 9 fromTable 1; compound 5 from Table 1 and compound 10 from Table 1; compound5 from Table 1 and compound 11 from Table 1; compound 5 from Table 1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 5 from Table 1 and FAIM;compound 5 from Table 1 and NOL3; compound 5 from Table 1 and DcR1;compound 5 from Table 1 and DcR2; compound 5 from Table 1 and DcR3;compound 6 from Table 1 and compound 7 from Table 1; compound 6 fromTable 1 and compound 8 from Table 1; compound 6 from Table 1 andcompound 9 from Table 1; compound 6 from Table 1 and compound 10 fromTable 1; compound 6 from Table 1 and compound 11 from Table 1; compound6 from Table 1 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 6 fromTable 1 and FAIM; compound 6 from Table 1 and NOL3; compound 6 fromTable 1 and DcR1; compound 6 from Table 1 and DcR2; compound 6 fromTable 1 and DcR3; compound 7 from Table 1 and compound 8 from Table 1;compound 7 from Table 1 and compound 9 from Table 1; compound 7 fromTable 1 and compound 10 from Table 1; compound 7 from Table 1 andcompound 11 from Table 1; compound 7 from Table 1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 7 from Table 1 and FAIM;compound 7 from Table 1 and NOL3; compound 7 from Table 1 and DcR1;compound 7 from Table 1 and DcR2; compound 7 from Table 1 and DcR3;compound 8 from Table 1 and compound 9 from Table 1; compound 8 fromTable 1 and compound 10 from Table 1; compound 8 from Table 1 andcompound 11 from Table 1; compound 8 from Table 1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 8 from Table 1 and FAIM;compound 8 from Table 1 and NOL3; compound 8 from Table 1 and DcR1;compound 8 from Table 1 and DcR2; compound 8 from Table 1 and DcR3;compound 9 from Table 1 and compound 10 from Table 1; compound 9 fromTable 1 and compound 11 from Table 1; compound 9 from Table 1 andH⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 9 from Table 1 and FAIM;compound 9 from Table 1 and NOL3; compound 9 from Table 1 and DcR1;compound 9 from Table 1 and DcR2; compound 9 from Table 1 and DcR3;compound 10 from Table 1 and compound 11 from Table 1; compound 10 fromTable 1 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4); compound 10 from Table1 and FAIM; compound 10 from Table 1 and NOL3; compound 10 from Table 1and DcR1; compound 10 from Table 1 and DcR2; compound 10 from Table 1and DcR3; compound 11 from Table 1 and H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO:4); compound 11 from Table 1 and FAIM; compound 11 from Table 1 andNOL3; compound 11 from Table 1 and DcR1; compound 11 from Table 1 andDcR2; compound 11 from Table 1 and DcR3; H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ IDNO: 4) and FAIM; H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4) and NOL3;H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4) and DcR1; H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQID NO: 4) and DcR2; H⁶⁰HIYLGATNYIY⁷¹-NH₂ (SEQ ID NO: 4) and DcR3; FAIMand NOL3; FAIM and DcR1; FAIM and DcR2; FAIM and DcR3; NOL3 and DcR1;NOL3 and DcR2; NOL3 and DcR3; and DcR1 and DcR2; DcR1 and DcR3; DcR2 andDcR3.

Some covalently linked combinations are represented by the followingstructural formulas:

P6-Met12  Formula C-1.

P6-Met12-P6  Formula C-2.

Met12-P6-Met12  Formula C-3.

P6-GGG-Met12  Formula C-4.

Met12-GGG-P6  Formula C-5.

P6-GGG-Met12-GGG-P6  Formula C-6.

Met12-GGG-P6-GGG-Met12  Formula C-7.

P6-(N-AEAc)_(x)-Met12  Formula C-8.

Met12-(N-AEEAc)_(x)-P6  Formula C-9.

Met12-(N-AEEAc)_(x)-P6-(N-AEEAc)_(y)-Met12  Formula C-10.

P6-(N-AEEAc)_(x)-Met12-(N-AEEAc)_(y)-P6  Formula C-11.

P6-(N-dPEG12)_(x)-Met12  Formula C-12.

P21-Met12  Formula C-13.

P21-Met12-P21  Formula C-14.

Met12-P21-Met12  Formula C-15.

P21-GGG-Met12  Formula C-16.

Met12-GGG-P21  Formula C-17.

P21-GGG-Met12-GGG-P21  Formula C-18.

Met12-GGG-P21-GGG-Met12  Formula C-19.

P21-(N-AEAc)_(x)-Met12  Formula C-20.

Met12-(N-AEEAc)_(x)-P21  Formula C-21.

Met12-(N-AEEAc)_(x)-P21-(N-AEEAc)_(y)-Met12  Formula C-22.

P21-(N-AEEAc)_(x)-Met12-(N-AEEAc)_(y)-P21  Formula C-23.

P21-(N-dPEG12)_(x)-Met12  Formula C-24.

P6-(O-AEAc)_(x)-Met12  Formula C-25.

Met12-(O-AEEAc)_(x)-P6  Formula C-26.

Met12-(O-AEEAc)_(x)-P6-(O-AEEAc)_(y)-Met12  Formula C-27.

P6-(O-AEEAc)_(x)-Met12-(O-AEEAc)_(y)-P6  Formula C-28.

P6-(O-dPEG12)_(x)-Met12  Formula C-29.

P21-(O-AEAc)_(x)-Met12  Formula C-30.

Met12-(O-AEEAc)_(x)-P21  Formula C-31.

Met12-(O-AEEAc)_(x)-P21-(O-AEEAc)_(y)-Met12  Formula C-32.

P21-(O-AEEAc)_(x)-Met12-(O-AEEAc)_(y)-P21  Formula C-33.

P21-(O-dPEG12)_(x)-Met12  Formula C-34.

P6-Met12-BC  Formula C-35.

P6-Met12-P6-BC  Formula C-36.

Met12-P6-Met12-BC  Formula C-37.

P6-GGG-Met12-BC  Formula C-38.

Met12-GGG-P6-BC  Formula C-39.

P6-GGG-Met12-GGG-P6-BC  Formula C-40.

Met12-GGG-P6-GGG-Met12-BC  Formula C-41.

P6-(N-AEAc)_(x)-Met12-BC  Formula C-42.

Met12-(N-AEEAc)_(x)-P6-BC  Formula C-43.

Met12-(N-AEEAc)_(x)-P6-(N-AEEAc)_(y)-Met12-BC  Formula C-44.

P6-(N-AEEAc)_(x)-Met12-(N-AEEAc)_(y)-P6-BC  Formula C-45.

P6-(N-dPEG12)_(x)-Met12-BC  Formula C-46.

P21-Met12-BC  Formula C-47.

P21-Met12-P21-BC  Formula C-48.

Met12-P21-Met12-BC  Formula C-49.

P21-GGG-Met12-BC  Formula C-50.

Met12-GGG-P21-BC  Formula C-51.

P21-GGG-Met12-GGG-P21-BC  Formula C-52.

Met12-GGG-P21-GGG-Met12-BC  Formula C-53.

P21-(N-AEAc)_(x)-Met12-BC  Formula C-54.

Met12-(N-AEEAc)_(x)-P21-BC  Formula C-55.

Met12-(N-AEEAc)_(x)-P21-(N-AEEAc)_(y)-Met12-BC  Formula C-56.

P21-(N-AEEAc)_(x)-Met12-(N-AEEAc)_(y)-P21-BC  Formula C-57.

P21-(N-dPEG12)_(x)-Met12-BC  Formula C-58.

P6-(O-AEAc)_(x)-Met12-BC  Formula C-59.

Met12-(O-AEEAc)_(x)-P6-BC  Formula C-60.

Met12-(O-AEEAc)_(x)-P6-(O-AEEAc)_(y)-Met12-BC  Formula C-61.

P6-(O-AEEAc)_(x)-Met12-(O-AEEAc)_(y)-P6-BC  Formula C-62.

P6-(O-dPEG12)_(x)-Met12-BC  Formula C-63.

P21-(O-AEAc)_(x)-Met12-BC  Formula C-64.

Met12-(O-AEEAc)_(x)-P21-BC  Formula C-65.

Met12-(O-AEEAc)_(x)-P21-(O-AEEAc)_(y)-Met12-BC  Formula C-66.

P21-(O-AEEAc)_(x)-Met12-(O-AEEAc)_(y)-P21-BC  Formula C-67.

P21-(O-dPEG12)_(x)-Met12-BC  Formula C-68.

BC-P6-Met12  Formula C-69.

BC-P6-Met12-P6  Formula C-70.

BC-Met12-P6-Met12  Formula C-71.

BC-P6-GGG-Met12  Formula C-72.

BC-Met12-GGG-P6  Formula C-73.

BC-P6-GGG-Met12-GGG-P6  Formula C-74.

BC-Met12-GGG-P6-GGG-Met12  Formula C-75.

BC-P6-(N-AEAc)_(x)-Met12  Formula C-76.

BC-Met12-(N-AEEAc)_(x)-P6  Formula C-77.

BC-Met12-(N-AEEAc)_(x)-P6-(N-AEEAc)_(y)-Met12  Formula C-78.

BC-P6-(N-AEEAc)_(x)-Met12-(N-AEEAc)_(y)-P6  Formula C-79.

BC-P6-(N-dPEG12)_(x)-Met12  Formula C-80.

BC-P21-Met12  Formula C-81.

BC-P21-Met12-P21  Formula C-82.

BC-Met12-P21-Met12  Formula C-83.

BC-P21-GGG-Met12  Formula C-84.

BC-Met12-GGG-P21  Formula C-85.

BC-P21-GGG-Met12-GGG-P21  Formula C-86.

BC-Met12-GGG-P21-GGG-Met12  Formula C-87.

BC-P21-(N-AEAc)_(x)-Met12  Formula C-88.

BC-Met12-(N-AEEAc)_(x)-P21  Formula C-89.

BC-Met12-(N-AEEAc)_(x)-P21-(N-AEEAc)_(y)-Met12  Formula C-90.

BC-P21-(N-AEEAc)_(x)-Met12-(N-AEEAc)_(y)-P21  Formula C-91.

BC-P21-(N-dPEG12)_(x)-Met12  Formula C-92.

BC-P6(O-AEAc)_(x)-Met12  Formula C-93.

BC-Met12(O-AEEAc)_(x)-P6  Formula C-94.

BC-Met12(O-AEEAc)_(x)-P6(O-AEEAc)_(y)-Met12  Formula C-95.

BC-P6(O-AEEAc)_(x)-Met12(O-AEEAc)_(y)-P6  Formula C-96.

BC-P6(O-dPEG12)_(x)-Met12  Formula C-97.

BC-P21(O-AEAc)_(x)-Met12  Formula C-98.

BC-Met12(O-AEEAc)_(x)-P21  Formula C-99.

BC-Met12(O-AEEAc)_(x)-P21(O-AEEAc)_(y)-Met12  Formula C-100.

BC-P21(O-AEEAc)_(x)-Met12(O-AEEAc)_(y)-P21  Formula C-101.

BC-P21(O-dPEG12)_(x)-Met12  Formula C-102.

For structural formulas C-1 to C-102 above, x is 1, 2, 3, 4, 5, 6, 7, 8,9, or 10; and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Bonding can occurat either end, or in any position, of Met12, P6, P21, or BC. P6, Met12,GGG, N-AEEAc, N-dPEG12, etc., represent the corresponding compound withthe structure modified to accommodate the bonding represented. Forexample,

P6 is Ac-VGDGGLFEKKL-NH₂ (SEQ ID NO: 1).

Met12 is

One potential structure for P6-Met12 (P6 and Met12 disclosed as SEQ IDNOS 1 and 3, respectively) is:

Some covalent linked compounds for use in a drug delivery systeminclude:

With respect to any relevant structural representation, such as FormulaC103 or C104, z is 0-10,000, 0-1,000, 1,000-2,000, 2,000-3,000,3,000-4,000, 4,000-5,000, 5,000-6,000, 6,000-7,000, 8,000-9,000,9,000-10,000, 0-5,000, or 5,000-10,000.

With respect to any relevant structural representation, such as FormulaC104, Y is N or O.

With respect to any relevant structural representation, such as FormulaC104, A¹ is P6, P21, or a group derived from C1-C34, e.g. with therelevant atoms removed to accommodate the bonding, as explained above.

With respect to any relevant structural representation, such as FormulaC104, A² is OCH₂CH₂O— or NHCH₂CH₂N—.

A sustained delivery component is the portion of the drug deliverysystem that allows the drug to remain in the body for a sustained periodof time, e.g. long beyond the time that it takes for the drug to bemetabolized or passed out of the body. Typically, a sustained deliverycomponent is an implant, such as a solid implant, that works byencapsulating or otherwise entrapping the drug into the implant. If theimplant is biodegradable or bioerodible, the drug may be released as theimplant biodegrades or bioerodes. The implant may also be porous sothat, over a period of time, drug may diffuse out of the implant.Biodegradable or bioerodible implants may be porous or non-porous.Typically, non-biodegradable or non-bioerodible implants are porous, andthe drug is released by diffusion. However, other mechanisms mayoperate, such as an osmotic pump.

The drug may be physically trapped in the sustained delivery componentand/or may be covalently bonded to a molecule that is part of thesustained delivery component.

Typical examples of biodegradable materials for porous or non-porousbiodegradable implants generally include, silica-based materials, ororganic biodegradable materials, such as polymers comprising poly(D,L-lactic acid) (PLA) and poly (D,L-lactic-co-glycolic acid)(PLGA),polyesteramide (PEA, DSM chemical), and polycaprolactone (PCL);hydrogels, such as polyvinyl alcohols (PVA), PEG amines,PEG-N-hydroxysuccinamide esters (like Ocular Therapeutix) and the like;collagen based materials (e.g. Euclid systems); or a combinationthereof.

There are a number of suitable silica based sustained deliverycomponents.

One type of silica based sustained delivery component includes a silicahydrogel composite obtainable by mixing silica particles, comprising anencapsulated drug, with a silica sol, wherein obtained hydrogelcomposite is shear-thinning. This type of delivery system is aninjectable, all-silica-based microparticle-silica hydrogel controlledrelease system which reduces the burst remarkably with different typesof encapsulated therapeutic and biologically active agents. Detaileddescriptions of this type of silica based sustained delivery component,and how they are made, are found in U.S. Pat. No. 9,949,922, issued onApr. 24, 2018 to Jokinen, et al., which is incorporated by referenceherein in its entirety.

Another type of silica based sustained delivery component includesflowing silica compositions and gels comprising a drug which areobtainable by method for producing a flowing silica compositionincluding a sol-gel transfer, where redispersion is carried out. Theredispersion includes adding, after having reached gel point of thesol-gel transfer, liquid into the gel formed by the sol-gel transfer,and the addition being made within a sufficiently short time periodafter reaching the gel point, to result, after mixing of the gel and theliquid, in a rheologically homogenous flowing silica composition, whichis and remains injectable as such, or by short stirring <30 s, through athin 22G needle. These flowing and injectable sustained delivery silicacompositions may increase the stability and preserve the activity ofencapsulated therapeutic agents. Detailed descriptions of this type ofsilica based sustained delivery component, and how it is made, is foundin United States Patent Application No. 20140057996, published Feb. 27,2014 by Jokinen, et al., which is incorporated by reference herein inits entirety.

Another type of silica based sustained delivery component comprises acomposition comprising a bioerodible porous silicon-based carriermaterial wherein the carrier material carries a drug and at least oneamorphous sugar, optionally further comprising a crystallizationinhibitor. These delivery systems comprise loading biomolecules into thepores of the silica carrier material, thus stabilizing the biomolecules.However, these systems may also be used for small molecule therapeuticcompounds. Detailed descriptions of this type of silica based sustaineddelivery component, and how it is made, is found in U.S. Pat. No.9,603,801, issued on Mar. 28, 2017 to Barnett, et al., which isincorporated by reference herein in its entirety.

Another type of silica based sustained delivery component includesbioerodible devices, such as implants for delivering drugs in acontrolled manner. The devices comprise a porous silicon-based carriermaterial impregnated or loaded with the drug. These particular siliconcarrier materials comprise at least one large molecule therapeutic agentdisposed in the pores of the carrier material. It is believed that theloading of large therapeutic molecule into the pores of the carriermaterial stabilizes the large molecules. In many embodiments, the largemolecule is a protein and the pores have an average size between about15 nm to about 40 nm, and the protein has a molecular weight from about100,000 amu to about 200,000 amu. However, these systems may also beused for small molecule therapeutic compounds. Detailed descriptions ofthis type of silica based sustained delivery component, and how it ismade, is found in U.S. Pat. No. 9,808,421, issued on Nov. 7, 2017, toAshton et al., U.S. Pat. No. 9,333,173 issued on May 10, 2016 to Ashtonet al., and United States Patent Publication No. 20140271764 publishedon Sep. 28, 2014 by Ashton, et al., all of which are incorporated byreference herein in its entirety.

The sustained delivery component may have any suitable mass, such asabout 10 μg-100 mg, about 10-20 μg, about 20-30 μg, about 30-40 μg,about 40-50 μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about80-90 μg, about 90-100 μg, about 100-200 μg, about 200-300 μg, about300-400 μg, about 400-500 μg, about 500-600 μg, about 600-700 μg, about700-800 μg, about 800-900 μg, about 900-1,000 μg, about 1-2 mg, about2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about7-8 mg, about 8-9 mg, about 9-10 mg, about 10-20 mg, about 20-30 mg,about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about70-80 mg, about 80-90 mg, about 90-100 mg, about 100-200 mg, about200-300 mg, about 300-400 mg, about 400-500 mg, about 500-600 mg, about600-700 mg, about 700-800 mg, about 800-900 mg, about 900-1,000 mg,about 1-2 g, about 2-3 g, about 3-4 g, about 4-5 g, about 5-6 g, about6-7 g, about 7-8 g, about 8-9 g, about 9-10 g, about 10-20 g, about20-30 g, about 30-40 g, about 40-50 g, about 50-60 g, about 60-70 g,about 70-80 g, about 80-90 g, about 90-100 g, about 100-200 g, about200-300 g, about 300-400 g, about 400-500 g, about 500-600 g, about600-700 g, about 700-800 g, about 800-900 g, about 900-1,000 g, about10-100 μg, about 100-1,000 μg, about 1-10 mg, about 10-100 mg, about100-1,000 mg, about 1-10 g, about 10-100 g, or about 100-1,000 g. Rangesabove which are about 1 g or less, or 100 mg or less, may be of interestfor drug delivery systems delivered onto or into the eye.

The sustained delivery component may be any suitable percentage of theimplant, such as about 1-99 wt %, about 1-10 wt %, about 10-20 wt %,about 20-30 wt %, about 30-40 wt %, about 40-50 wt %, about 50-60 wt %,about 60-70 wt %, about 70-80 wt %, about 80-90 wt %, about 90-99 wt %,about 1-30 wt %, about 30-65 wt %, about 65-99 wt %, about 1-50 wt %, orabout 50-99 wt %.

The drug delivery system may be of any suitable size, such as about 10μg-100 mg, about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg,about 90-100 μg, about 100-200 μg, about 200-300 μg, about 300-400 μg,about 400-500 μg, about 500-600 μg, about 600-700 μg, about 700-800 μg,about 800-900 μg, about 900-1,000 μg, about 1-2 mg, about 2-3 mg, about3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about8-9 mg, about 9-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg,about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about80-90 mg, about 90-100 mg, about 100-200 mg, about 200-300 mg, about300-400 mg, about 400-500 mg, about 500-600 mg, about 600-700 mg, about700-800 mg, about 800-900 mg, about 900-1,000 mg, about 1-2 g, about 2-3g, about 3-4 g, about 4-5 g, about 5-6 g, about 6-7 g, about 7-8 g,about 8-9 g, about 9-10 g, about 10-20 g, about 20-30 g, about 30-40 g,about 40-50 g, about 50-60 g, about 60-70 g, about 70-80 g, about 80-90g, about 90-100 g, about 100-200 g, about 200-300 g, about 300-400 g,about 400-500 g, about 500-600 g, about 600-700 g, about 700-800 g,about 800-900 g, about 900-1,000 g, about 10-100 μg, about 100-1,000 μg,about 1-10 mg, about 10-100 mg, about 100-1,000 mg, about 1-10 g, about10-100 g, or about 100-1,000 g. Ranges above which are about 1 g orless, or 100 mg or less, may be of interest for drug delivery systemsdelivered onto or into the eye.

Typical examples of non-biodegradable or non-bioerodible materials forimplants include silicones or PVA as semipermeable membranes (likePsivida).

Other potential sustained delivery components could be based uponcell-based approaches like encapsulated cell technology; and reservoirtype approaches (forsight4; Replenish).

The prostaglandin compound or prostaglandin receptor agonist, theintraocular pressure lowering agent, and/or the neurotrophic agent, suchas the CNTF compound, may, or may not, be covalently attached to thesustained delivery component.

In some embodiments, the prostaglandin compound or prostaglandinreceptor agonist is covalently attached to the sustained deliverycomponent. In some embodiments, the prostaglandin compound orprostaglandin receptor agonist is not covalently attached to thesustained delivery component.

In some embodiments, the intraocular pressure lowering agent iscovalently attached to the sustained delivery component. In someembodiments, the intraocular pressure lowering agent is not covalentlyattached to the sustained delivery component.

In some embodiments, the neurotrophic agent, such as the CNTF compound,is covalently attached to the sustained delivery component. In someembodiments, the neurotrophic agent, such as the CNTF compound, is notcovalently attached to the sustained delivery component.

For example, a prostaglandin compound or prostaglandin receptor agonistmay be covalently attached to the sustained delivery component using acompound represented by a formula:

wherein PG-H is a prostaglandin compound or prostaglandin receptoragonist, such as a prostaglandin compound or prostaglandin receptoragonist recited above.

Compounds of Formula 3 may be further represented by Formula 3A and 3B:

wherein Prg-CO₂H is a prostaglandin agonist and n is 1, 2, 3, 4, 5, 6,7, 8, 9, 10, etc.

An intraocular pressure lowering agent may be covalently attached to thesustained delivery component using a compound represented by a formula:

wherein IOP-H is an intraocular pressure lowering agent, such as anintraocular pressure lowering agent recited above.

A CNTF compound or another neurotrophic agent may be covalently attachedto the sustained delivery component using a compound represented by aformula:

wherein CNTF-H is a CNTF compound or another neurotrophic agent, such asa CNTF compound or another neurotrophic agent recited above.

A CNP compound may be covalently attached to the sustained deliverycomponent using a compound represented by a formula:

wherein CNP-H is a CNP compound.

An NPR-B compound may be covalently attached to the sustained deliverycomponent using a compound represented by a formula:

wherein NPRB-H is a NRP-B compound.

With respect to any relevant structural representation, such as Formula3, 3A, 3B, 4, 5, 6, or 7, or the compounds depicted below, R¹ isindependently H or C₁₋₆ alkyl, such as CH₃, C₂ alkyl, C₃ alkyl, C₄alkyl, C₅ alkyl, or C₆ alkyl.

With respect to any relevant structural representation, such as Formula3, 3A, 3B, 4, 5, 6, or 7, or the compounds depicted below, R² isindependently H or C₁₋₆ alkyl, such as CH₃, C₂ alkyl, C₃ alkyl, C₄alkyl, C₅ alkyl, or C₆ alkyl.

With respect to any relevant structural representation, such as Formula3, 3A, 3B, 4, 5, 6, or 7, or the compounds depicted below, and R³ isindependently H or C₁₋₆ alkyl, such as CH₃, C₂ alkyl, C₃ alkyl, C₄alkyl, C₅ alkyl, or C₆ alkyl.

The compounds are examples of compounds of Formula 3, 3A or 3B:

In the body, the ester bond can hydrolyze to release the compound:

The table below shows three compounds that are examples of compounds ofFormula 4, and the three compounds that can be released in the body byhydrolysis of the ester or amide group:

Compound of Formula 4 Compound released in body

In the table above, any Si(OH)₃ group may be replaced with SiOR¹O R²OR³.An example of a compound of Formula 5 is: VGDGGLFEKKL-PEG-Si(OH)₃(“VGDGGLFEKKL” disclosed as SEQ ID NO: 1) or VGDGGLFEKKL-PEG-SiOR¹O R²OR³ (“VGDGGLFEKKL” disclosed as SEQ ID NO: 1) wherein PEG is apolyethylene glycol chain (e.g. (OCH₂CH₂)_(n)—, where n is 1, 2, 3, 4,5, 6, 7, 8, 9, 10, etc.). In the body, the ester bond can hydrolyze torelease VGDGGLFEKKL (SEQ ID NO: 1).

The SiOR¹O R²O R³ group of Formulas 3, 3A, 3B, 4, 5, 6, or 7 may becovalently bonded to the silica of a silica based drug delivery system,e.g. to form compounds represented by Formulas 3D, 3AD, 3BD, 4D, or 5D,wherein D is a sustained delivery component comprising the Si of theSiOR¹O R²O R³ of Formula 3, 3A, 3B, 4, 5, 6, or 7.

Some drug delivery systems may be comprise a polymer represented by aformula:

wherein each X is independently

A subject drug delivery system may be administered to a mammal, such asa human, by any suitable method, such as by injection or surgicalimplantation into any part of the body, oral administration, or topicalapplication to the eye or skin. In some embodiments, an implant isinjected or otherwise implanted in or around an eye, including but notlimited to: the anterior chamber, the vitreous, the posterior chamber,the subconjunctival space, the suprachoroidal space, or subtenon'sspace.

A subject drug delivery system may extend the amount of time that thedrug remains in the body. For example, a drug delivery system mayprovide therapeutic levels of the drug for at least about 2 weeks, atleast about 4 weeks, at least about 6 weeks, at least about 8 weeks, atleast about 3 months, at least about 4 months, at least about 5 months,at least about 6 months, at least about 7 months, at least about 8months, at least about 9 months, at least about 10 months, at leastabout 11 months, at least about 1 year, at least about 1.5 years, atleast about 2 years, at least about 3 years, at least about 4 years,about 1-6 months, about 6-12 months, about 12-18 months, about 18-24months, about 24-36 months, up to about 2 years, up to about 3 years, upto about 4 years, up to about 5 years, or up to about 10 years. The drugdelivery system may be injected, implanted, or changed at a time in anyof the ranges above.

In some embodiments, a subject drug delivery system may be administeredto a mammal, such as a human being, to treat a glaucoma, such as PrimaryOpen-Angle Glaucoma (POAG), Acute Primary Angle Close Glaucoma (APACG),Chronic Angle Closure Glaucoma, Pigmentary Glaucoma, PseudoexfoliationGlaucoma, Normal Tension Glaucoma, Pediatric Glaucoma, a secondaryglaucoma, etc., or a combination thereof.

EXAMPLES

The following examples are intended to be illustrative of theembodiments of the disclosure, but are not intended to limit the scopeor underlying principles in any way.

Example 1: Solid Phase Synthesis of a PG-L-CNTF Featuring an AmideLinkage

Using methods known in the art, peptide 6 is linked to a resin at theNH₂ terminus, is protected with BOC groups and t-Bu ester groups, andlinked to NH₂-terminated-PEG at the carboxylic acid terminus to provideResin-L-K(Boc)-K(Boc)-E(tBu)-F-L-G-G-D(tBu)-G-V-CO₂(CH₂—CH₂—O)_(n)—CH₂—CH₂—NH₂.The nature of the starting materials, and the order of reactions may bemodified to improve efficiency and selectivity, and all reactions areconducted using methods known in the art. Bimatoprost free acid, havingits three hydroxyl groups protected with t-butyl groups (or other alkyl-or silyl-protecting groups, as appropriate), is prepared by methodsknown in the art. The free amine of the protected peptide 6 compound andthe free acid of the protected prostaglandin compound may be coupled byany appropriate peptide coupling method known in the art. Following thecoupling reaction, the protected amide can be fully deprotected usingTFA or other acid-catalyzed methods know in the art to release thePeptide 6-Linker-Bimatoprost amide derivative. Different orthogonalprotecting group strategies may be employed as necessary, as known inthe art, to optimize the efficiency of the overall procedure.

Example 2: Solid Phase Synthesis of a PG-L-CNTF Featuring an EsterLinkage

Using methods known in the art, peptide 6 is linked to a resin at theNH₂ terminus, is protected with CBz groups on the free amine groups andbenzyl groups on the free acid groups, and is coupled to polyethyleneglycol at the carboxylic acid terminus to provideResin-L-K(Cbz)-K(Cbz)-E(Bn)-F-L-G-G-D(Bn)-G-V-CO₂(CH₂—CH₂—O)_(n)—CH₂—CH₂—OH.The nature of the starting materials and the order of reactions may bemodified to improve selectivity, and all reactions are conducted usingmethods known in the art. Bimatoprost free acid, having its threehydroxyl groups protected with benzyl groups (or otherhydrogenation-labile protecting groups, as appropriate), is prepared bymethods known in the art. The free alcohol terminus of the protectedpeptide 6 compound and the free acid of the protected prostaglandincompound may be coupled by any appropriate ester coupling method knownin the art. Following the coupling reaction, the protected ester can befully deprotected using hydrogenation methods or other debenzylationmethods known in the art to release the Peptide 6-Linker-Bimatoprostester derivative. Different orthogonal protecting group strategies maybe employed as necessary, as known in the art, to optimize theefficiency of the overall procedure.

The following embodiments are specifically contemplated by theinventors:

Embodiment 1. A drug delivery system comprising an intraocular pressurelowering agent, a neurotrophic agent, a C-type Natriuretic Peptide(CNP), a Natriuretic Peptide Receptor-B (NPR-B), or an apoptosissignaling fragment inhibitor (FAS) or FAS-ligand (FASL) inhibitor, and asustained delivery component.Embodiment 2. The drug delivery system of Embodiment 1, comprising theintraocular pressure lowering agent.Embodiment 3. The drug delivery system of Embodiment 2, wherein theintraocular pressure lowering agent is a prostaglandin compound.Embodiment 4. The drug delivery system of Embodiment 2 or 3, furthercomprising a second intraocular pressure lowering agent.Embodiment 5. The drug delivery system of Embodiment 2, 3, or 4, whereinthe intraocular pressure lowering agent comprises a beta blocker.Embodiment 6. The drug delivery system of Embodiment 2, 3, 4, or 5,wherein the intraocular pressure lowering agent comprises timolol.Embodiment 7. The drug delivery system of Embodiment 2, 3, 4, 5, or 6,wherein the intraocular pressure lowering agent comprises betaxolol.Embodiment 8. The drug delivery system of Embodiment 2, 3, 4, 5, 6, or7, wherein the intraocular pressure lowering agent compriseslevobunolol.Embodiment 9. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,or 8, wherein the intraocular pressure lowering agent comprisesmetipranolol.Embodiment 10. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, or 9, wherein the intraocular pressure lowering agent comprises analpha adrenergic agonist.Embodiment 11. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, or 10, wherein the intraocular pressure lowering agent comprisesbrimonidine.Embodiment 12. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, or 11, or 10, wherein the intraocular pressure lowering agentcomprises apraclonidine.Embodiment 13. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12, wherein the intraocular pressure lowering agentcomprises a carbonic anhydrase inhibitor.Embodiment 14. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, or 13, wherein the intraocular pressure lowering agentcomprises brinzolamide.Embodiment 15. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, or 14, wherein the intraocular pressure loweringagent comprises acetazolamide.Embodiment 16. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15, wherein the intraocular pressurelowering agent comprises dorzolamide.Embodiment 17. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the intraocular pressurelowering agent comprises methazolamide.Embodiment 18. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the intraocularpressure lowering agent comprises a cholinergic.Embodiment 19. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the intraocularpressure lowering agent comprises pilocarpine.Embodiment 20. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the intraocularpressure lowering agent comprises carbachol.Embodiment 21. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein theintraocular pressure lowering agent comprises a Rho Kinase (ROCK)inhibitor.Embodiment 22. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein theintraocular pressure lowering agent comprises netarsudil.Embodiment 23. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22,comprising the neurotrophic agent.Embodiment 24. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23,comprising both the prostaglandin receptor agonist and the neurotrophicagent.Embodiment 25. The drug delivery system of Embodiment 24, wherein theprostaglandin receptor agonist and the neurotrophic agent are covalentlybound to one another.Embodiment 26. The drug delivery system of Embodiment 25, wherein theprostaglandin receptor agonist and the neurotrophic agent are covalentlybound to one another via a linking group.Embodiment 27. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or26, wherein the prostaglandin receptor agonist comprises bimatoprost.Embodiment 28. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or26, wherein the prostaglandin receptor agonist comprises travoprost.Embodiment 29. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or26, wherein the prostaglandin receptor agonist comprises latanoprost.Embodiment 30. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or26, wherein the prostaglandin receptor agonist comprises latanoprostene.Embodiment 31. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or26, wherein the prostaglandin receptor agonist comprises tafluprost.Embodiment 32. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or26, wherein the prostaglandin receptor agonist comprises a prostaglandinEP2 receptor agonist.Embodiment 33. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or26, wherein the prostaglandin receptor agonist comprises a prostaglandinEP3 receptor agonist.Embodiment 34. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, or 33, wherein the neurotrophic agentcomprises CNTF Peptide 6.Embodiment 35. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the neurotrophic agentcomprises CNTF Peptide 21.Embodiment 36. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, comprising the CNP compound.Embodiment 37. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, comprising the NPR-Bcompound.Embodiment 38. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37, comprising both theintraocular pressure lowering agent and the neurotrophic agent.Embodiment 39. The drug delivery system of Embodiment 38, wherein theintraocular pressure lowering agent and the neurotrophic agent arecovalently bound to one another.Embodiment 40. The drug delivery system of Embodiment 39, wherein theintraocular pressure lowering agent and the neurotrophic agent arecovalently bound to one another via a linking group.Embodiment 41. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40,comprising both the intraocular pressure lowering agent and the CNPcompound.Embodiment 42. The drug delivery system of Embodiment 41, wherein theintraocular pressure lowering agent and the CNP compound are covalentlybound to one another.Embodiment 43. The drug delivery system of Embodiment 42, wherein theintraocular pressure lowering agent and the CNP compound are covalentlybound to one another via a linking group.Embodiment 44. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or43, comprising both the intraocular pressure lowering agent and theNPR-B compound.Embodiment 45. The drug delivery system of Embodiment 44, wherein theintraocular pressure lowering agent and the NPR-B compound arecovalently bound to one another.Embodiment 46. The drug delivery system of Embodiment 45, wherein theintraocular pressure lowering agent and the NPR-B compound arecovalently bound to one another via a linking group.Embodiment 47. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, or 46, comprising both the neurotrophic agent and the CNPcompound.Embodiment 48. The drug delivery system of Embodiment 47, wherein theneurotrophic agent and the CNP compound are covalently bound to oneanother.Embodiment 49. The drug delivery system of Embodiment 48 wherein theneurotrophic agent and the CNP compound are covalently bound to oneanother via a linking group.Embodiment 50. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, or 49, comprising both the neurotrophic agent andthe NPR-B compound.Embodiment 51. The drug delivery system of Embodiment 50, wherein theneurotrophic agent and the NPR-B compound are covalently bound to oneanother.Embodiment 52. The drug delivery system of Embodiment 51, wherein theneurotrophic agent and the NPR-B compound are covalently bound to oneanother via a linking group.Embodiment 53. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, or 52, comprising both the CNP compoundand the NPR-B compound.Embodiment 54. The drug delivery system of Embodiment 53, wherein theCNP compound and the NPR-B compound are covalently bound to one another.Embodiment 55. The drug delivery system of Embodiment 54, wherein theCNP compound and the NPR-B compound are covalently bound to one anothervia a linking group.Embodiment 56. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, wherein theneurotrophic agent is a CNTF compound.Embodiment 57. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is silica based.Embodiment 58. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is porous.Embodiment 59. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is non-porous.Embodiment 60. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is of the type described in U.S. Pat. No.9,949,922, issued on Apr. 24, 2018 to Jokinen, et al.Embodiment 61. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is of the type described in United StatesPatent Application Publication No. 20140057996, published Feb. 27, 2014by Jokinen, et al.Embodiment 62. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is of the type described in U.S. Pat. No.9,603,801, issued on Mar. 28, 2017 to Barnett, et al.,Embodiment 63. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is of the type described in U.S. Pat. No.9,808,421, issued on Nov. 7, 2017, to Ashton et al.Embodiment 64. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is of the type described in U.S. Pat. No.9,333,173 issued on May 10, 2016 to Ashton et al.Embodiment 65. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein thesustained delivery component is of the type described in United StatesPatent Publication No. 20140271764 published on Sep. 28, 2014 by Ashton,et al.Embodiment 66. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, or 65, wherein the prostaglandin receptor agonist iscovalently attached to the sustained delivery component.Embodiment 67. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, or 66, wherein the neurotrophic agent is covalentlyattached to the sustained delivery component.Embodiment 68. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, or 67, wherein the prostaglandin receptor agonist is notcovalently attached to the sustained delivery component.Embodiment 69. The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, or 68 wherein the neurotrophic agent is notcovalently attached to the sustained delivery component.Embodiment 70. A method of treating a glaucoma or ocular hypertensioncomprising administering a drug delivery system of Embodiment 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69 to a mammal suffering fromglaucoma or ocular hypertension.Embodiment 71. The method of Embodiment 70, wherein the drug deliverysystem is administered by intravitreal injection into an affected eye ofthe mammal.Embodiment 72. The method of Embodiment 70, wherein the drug deliverysystem is implanted into the anterior chamber, the subconjunctivalspace, the suprachoroidal space, or the subtenon's space of an affectedeye of the mammal.Embodiment 73. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises Primary Open-Angle Glaucoma (POAG).Embodiment 74. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises Acute Primary Angle Close Glaucoma (APACG).Embodiment 75. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises Chronic Angle Closure Glaucoma.Embodiment 76. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises Pigmentary Glaucoma.Embodiment 77. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises Pseudoexfoliation Glaucoma.Embodiment 78. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises Normal Tension Glaucoma.Embodiment 79. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises Pediatric Glaucoma.Embodiment 80. The method of Embodiment 70, 71, or 72, wherein theglaucoma comprises a secondary glaucoma.

1. A drug delivery system comprising: a first active pharmaceuticalingredient (API) and a sustained delivery component, wherein the firstAPI is an intraocular pressure lowering agent, a neurotrophic agent, aC-type Natriuretic Peptide (CNP), a Natriuretic Peptide Receptor-B(NPR-B), an apoptosis signaling fragment (FAS) inhibitor or a FAS-ligand(FASL) inhibitor, or a combination thereof.
 2. The drug delivery systemof claim 1, further comprising a second API, wherein the first API isthe intraocular pressure lowering agent and the second API is theneurotrophic agent.
 3. The drug delivery system of claim 1, furthercomprising a second API, wherein the first API is the intraocularpressure lowering agent and the second API is the CNP.
 4. The drugdelivery system of claim 1, further comprising a second API, wherein thefirst API is the intraocular pressure lowering agent and the second APIis the NPR-B.
 5. The drug delivery system of claim 1, further comprisinga second API, wherein the first API is the intraocular pressure loweringagent and the second API is the FAS inhibitor or the FASL inhibitor. 6.The drug delivery system of claim 1, further comprising a second API,wherein the first API is the neurotrophic agent and the second API isthe CNP.
 7. The drug delivery system of claim 1, further comprising asecond API, wherein the first API is the neurotrophic agent and thesecond API is the NRP-B.
 8. The drug delivery system of claim 1, furthercomprising a second API, wherein the first API is the neurotrophic agentand the second API is the FAS inhibitor or the FASL inhibitor.
 9. Thedrug delivery system of claim 1, further comprising a second API,wherein the first API is the CNP and the second API is the NRP-B. 10.The drug delivery system of claim 1, further comprising a second API,wherein the first API is the CNP and the second API is the FAS inhibitoror the FASL inhibitor.
 11. The drug delivery system of claim 1, furthercomprising a second API, wherein the first API is the NRP-B and thesecond API is the FAS inhibitor or the FASL inhibitor.
 12. The drugdelivery system of claim 1, further comprising a second API, wherein thefirst API and the second API are not covalently bonded to one another.13. The drug delivery system of claim 1, further comprising a secondAPI, wherein the first API is covalently bonded to the second API. 14.The drug delivery system of claim 1, wherein the first API is covalentlybonded to the sustained delivery component.
 15. The drug delivery systemof claim 1, further comprising a second API, wherein the second API iscovalently bonded to the sustained delivery component.
 16. The drugdelivery system of claim 1, having about 100 μg to about 1 mg of thefirst API.
 17. The drug delivery system of claim 1, further comprising asecond API, having about 100 μg to about 1 mg of the second API.
 18. Thedrug delivery system of claim 1, wherein the implant has a weight ofabout 300 μg to about 10 mg.
 19. A method of treating a glaucomacomprising administering a drug delivery system of claim 1, to a mammalin suffering from glaucoma or ocular hypertension.
 20. The method ofclaim 19, wherein the drug delivery system is injected into an eye ofthe mammal, and wherein the mammal is a human being. 21.-26. (canceled)